JPH0733357B2 - Cinnamic acid derivative - Google Patents

Description

The present invention relates to a novel cinnamic acid derivative, and more specifically, it has the following general formula (I) having excellent antiallergic activity. In the formula, R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, provided that R ¹ , R ² and R ³ represent hydrogen atoms at the same time. None; Or Represents where Represents an unsubstituted or substituted alicyclic hydrocarbon ring optionally having a double bond in the ring; Y represents a 3- (hydroxy or acetoxy) indol-1-yl group, a carboxyalkyleneamino group Or Wherein X represents —NH— or —O—, R ⁶ represents a carboxyl group or a tetrazolyl group, and a salt thereof.

The present inventors have conducted research such as development of an anti-allergic agent that suppresses the release of chemical mediators induced by an antigen-antibody reaction and elucidation of the oxygen reaction mechanism involved in the anti-allergic action. , That some anthranilic acid analogs suppress the release of histamine from mast cells and at the same time suppress the contraction of the trachea induced by the antigen (allergen), As a result of the investigation, this time, a group of cinnamic acid derivatives represented by the general formula (I) stabilizes mast cells, suppresses histamine release therefrom, and also causes allergen-induced tracheal contraction. The present invention was completed by discovering that it has an inhibitory action and is extremely promising as an antiallergic agent.

Therefore, the present invention provides a compound having the antiallergic activity represented by the general formula (I).

In the general formula (I), the “alkyl group” may be linear or branched and is preferably a lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl and n-. Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
It includes isopentyl, n-hexyl, isohexyl groups and the like.

An "alkoxy group" is an alkyloxy group in which the alkyl part has the meanings given above, for example methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, sec
Examples thereof include -butoxy and tert-butoxy groups, and among them, a methoxy group is preferable.

The "halogen atom" includes chlorine, bromine, fluorine and iodine atoms, and chlorine and bromine atoms are particularly preferable.

The alkylene moiety in the “carboxyalkyleneamino group” may be linear or branched, and may be a lower alkylene having 1 to 6 carbon atoms, for example, —CH ₂ CH ₂ , —CH ₂ CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₃ CH ₂ — and the like. Thus, specific examples of the carboxy alkylene amino group is, for example _{-NHCH 2 CH 2 COOH, -NHCH 2} CH 2 CH 2 COOH, Etc.

In the general formula (I), The "unsubstituted or substituted alicyclic hydrocarbon ring optionally having a double bond in the ring" is preferably 5 to 8 such as cyclopentyl ring and cyclohexyl ring.
Membered alicyclic hydrocarbon ring, which ring may have one or two double bonds at any position, and a carbon atom as a substituent on the ring. There may be 1 to 4 alkyl groups such as methyl groups and other groups present. Then, in the specific examples of the alicyclic hydrocarbon ring, Etc.

Among the compounds represented by the general formula (I) provided by the present invention, a particularly preferred group of compounds is that R ¹ and R ² are each a methoxy group and R ³ is a hydrogen atom, or R ¹ is an n-pentyl group, R ² and R ³ are hydrogen atoms, And Y represents a 3- (hydroxy) indol-1-yl group, a 3- (acetoxy) indol-1-yl group, 2-
Carbonylethylamino group, (R ⁶ is a tetrazolyl group) included in the group of compounds. Particularly preferred compounds, R ¹ and R ² are methoxy groups and R ³ is a hydrogen atom, Indicates that Y is (R ⁶ is a tetrazolyl group).

In the above general formula (I), Is a double bond, the groups existing across this double bond And the group -CO-Y are in cis configuration with respect to each other (ie, Z-configuration)
It is preferable to have

Typical examples of the compound represented by the above formula (I) provided by the present invention include the following.

3-[(Z) -3,4-dimethoxycinnamoylamino]
Propionic acid; 3-[(Z) -4-pentylcinnamoylamino] propionic acid; 2-[(Z) -3,4-dimethoxycinnamoyloxy]
Benzoic acid; 2-[(Z) -4-pentylcinnamoyloxy] benzoic acid; N-[(Z) -3,4-dimethoxycinnamoyl] -2-
(Tetrazol-5-yl) aniline; 3-acetoxy-1-[(Z) -3,4-dimethoxycinnamoyl] indole; 3-acetoxy-1-[(Z) -4-pentylcinnamoyl] indole; 1 -[(Z) -3,4-dimethoxycinnamoyl] -3-
Hydroxyindole; 1-[(Z) -4-dimethoxycinnamoyl] -3-hydroxyindole; N-[(Z) -4-pentylcinnamoyl] anthranilic acid; N-[(E) -4-pentylcinnamoyl ] Anthranilic acid; N- [2- (3,4-dimethoxyphenyl) cyclohexylcarbonyl] anthranilic acid; N- [2- (4-Pentylphenyl) cyclohexylcarbonyl] anthranilic acid; N- [2- (3, 4-dimethoxyphenyl) -4,5-dimethyl-4-cyclohexenylcarbonyl] anthranilic acid; N- [2- (3,4-dimethoxyphenyl-3-cyclohexenylcarbonyl] anthranilic acid; N-[(Z ) -2-Bromo-3,4-dimethoxycinnamoyl] anthranilic acid; N- (3-Bromo-4,5-dimethoxyphenylpropio N-[(Z) -3-Bromo-4,5-dimethoxycinnamoyl] anthranilic acid; N- (4-chlorophenylpropioroyl) anthranilic acid; N- [2- (3,4 -Dimethoxyphenyl) -4,5-dimethyl-4-cyclohexenoyl] anthranilic acid; N- [2- (3,4-dimethoxyphenyl) -3-cyclohexenoyl] anthranilic acid and the like.

When Y is a carboxyalkyleneamino group or R ⁶ is a carboxy group The compounds of formula (I) in which can be present can exist in the form of salts. Such salts include alkali metal salts such as sodium, potassium and lithium; alkaline earth metal salts such as calcium and magnesium; organic amine salts such as cyclohexylamine, trimethylamine and diethanolamine; basic amino acid salts such as arginine and lysine. An ammonium salt and the like are exemplified. The compound represented by the general formula (I) provided in the present invention is, for example, the compound represented by the general formula (II) Where R ¹ , R ² , R ³ and Has the same meaning as defined above, and a carboxylic acid or a reactive derivative thereof represented by the formula (II
I) YH (III) In the formula, Y has the same meaning as defined above, and can be produced by reacting with a compound represented by or a reactive derivative at an amino group or a hydroxyl group.

The reaction of the carboxylic acid of formula (II) with the compound of formula (III) is basically an amidation reaction (when the compound of formula (III) is an amine) or an esterification reaction (of formula (III)). When the compound is an alcohol), it can be carried out according to an amidation reaction or esterification reaction known per se.

Thus, the reactive derivative of the carboxylic acid represented by the formula (II) may be a reactive derivative of the type usually used in an amidation reaction or an esterification reaction, such as an acid halide or an acid anhydride. , Mixed acid anhydrides,
Examples thereof include active esters.

The carboxylic acid of the formula (II) or its reactive derivative and the formula (II
The reaction with the compound of I) depends on whether the carboxylic acid of formula (II) is used in the free acid form or in the form of its reactive derivative, etc., as in the usual amidation or esterification reactions. Generally, the reaction can be carried out in a solvent using a reaction catalyst or a reaction accelerator.

For example, when using a halide of a carboxylic acid represented by the formula (II), the reaction is carried out in the presence of a base as an acid binder in an inert solvent, or in a large excess of an organic base which also serves as a solvent, such as pyridine or triethylamine. Reacting with a compound of formula (III) in a tertiary amine, or reacting with a compound of formula (III) in an amount of at least 2 times the molar amount of a carboxylic acid halide in an inert solvent without using a base. Can be done by.

Examples of the base that can be used in the above reaction include tertiary amines such as triethylamine and pyridine; sodium carbonate,
Inorganic bases such as potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like can be mentioned, and examples of the inert solvent usable in the reaction include methylene chloride, chloroform, benzene, toluene and xylene. , Tetrahydrofuran, dioxane,
Dimethylformamide, acetone, acenitrile and the like can be mentioned, and these can be used alone or as a mixed solvent.

Although the reaction temperature cannot be generally stated, it is convenient to carry out the reaction at a temperature in the range of room temperature to the reflux temperature of the reaction mixture, usually in the range of about 60 ° C to about 120 ° C.

Alternatively, the carboxylic acid represented by the formula (II) is reacted with a halogenated lower fatty acid ester, for example, a chloroformic acid ester, preferably isobutyl chloroformate in the presence of a base to convert the carboxylic acid into an acid anhydride in advance. It is also possible to derive and then react the acid anhydride with a compound of formula (III). The base that can be used in the reaction in this case is preferably a tertiary amine such as triethylamine or pyridine, and is preferably carried out in the coexistence of a solvent that does not directly influence the reaction. Examples of such a solvent include the above-mentioned inert solvents, and among them, tetrahydrofuran and dimethylformamide are preferable. In this production method, the acid anhydride of the carboxylic acid represented by the formula (II) can be subjected to the reaction with the compound of the formula (III) without isolation at the stage of deriving the acid anhydride.

The compound represented by the above formula (I) produced by the above-mentioned production method is separated and purified from the reaction mixture by a method known per se, for example, means such as concentration, washing, extraction, recrystallization and chromatography. can do.

As described above, the compound represented by the formula (I) provided by the present invention is preferably a compound having a cis configuration (Z-form), and therefore, the compound represented by the formula (II) which is a starting material in the above production method. It is preferable to use a compound having a cis configuration even in the carboxylic acid represented by In this case, the formula (I
The cis-configured carboxylic acid represented by I) causes a photoisomerization reaction by irradiating a corresponding easily-available carboxylic acid (E-form) in the trans configuration with a desired cis-configuration. It can be produced by introducing a carboxylic acid having a configuration. The light used for the light irradiation is, for example, at least 310 to 315 nm and / or 360 to 370 n.
Light containing ultraviolet radiation having a wavelength of m, especially about 313 nm and / or about 366 nm is preferred.

The compound represented by the above formula (I) produced as described above is a novel compound which has not been described in the literature, stabilizes mast cells, suppresses histamine release, and is further induced by an antigen (allergen) trachea. It also has an action of suppressing the contraction of erythrocyte and is useful as an antiallergic agent.

The excellent pharmacological effect of the compound represented by the formula (I) provided in the present invention can be verified by the following pharmacological tests.

(1) Inhibitory effect of histamine release from rat mast cells by Compound 48/80 Using SD male rat with a body weight of 200-250 g, the blood was killed and 50 ml of physiological solution [containing heparin 20 unit / ml] of pH 7.0 was added. After injecting into the abdominal cavity and pine surge in the abdomen for about 2 minutes, a cell suspension containing cells in the abdominal cavity was aspirated. Then, the liquid was used to purify mast cells using the Percoll density gradient method. Next, the number of purified mast cells was adjusted to 4 × 10 ⁴ cells / test tube, and the following experiment was performed.

The above suspension was pre-incubated with the test drug obtained in the Examples below at 37 ° C for 15 minutes, Compound 48/80 was added, and the mixture was further incubated at 37 ° C for 15 minutes. The reaction was stopped with ice-cooling, and the amount of free histamine in the supernatant was adjusted to Shore.
Et al. [Journal of Pharmacology and Experimental Terraputicus (J.of
Pharmacology and Experimental Therapeutics) 22
(2), 89, 1978] (fluorometer: Hitachi model F-3000).

The results are shown in Table 1 below. As a control, tranilast and its cis form (cistranilast) were used.

(2) Inhibitory effect on antigen-induced contraction of isolated guinea pig trachea A piece of trachea was removed from a male guinea pig weighing 400 to 1,000 g, and the guinea pig was treated with anti-ovalbumin serum (IgE) and oxygen 95% -5% carbon dioxide at room temperature. Incubate for 2 hours in the atmosphere.

The extirpated tracheal piece was placed in Krebs-H
ensleit) solution is placed in a 10 ml reactor, and a 95% oxygen-5% carbon dioxide gas stream is ventilated through the reactor. Then, the test drug was administered into the reactor and treated for 5 minutes, the antigen was administered in the same manner, and the contraction of the trachea was recorded on a chymograph to calculate the yield inhibition rate.

The results are shown in Table 2 below. In addition, tranilast and its cis form (cis-tranilast) were used as control drugs.

As is clear from the above pharmacological data, the formula (I) of the present invention is
The compounds represented by have useful antiallergic activity. Therefore, the compound of the present invention can be a useful antiallergic agent.

The present invention will be further described below with reference to Reference Examples and Examples.

Reference Example 1: (E) -3,4-dimethoxycinnamic acid 3,4-dimethoxybenzaldehyde 50.5 g (301 mM) and malonic acid 61.5 g (591 mM) were dissolved in 121 ml of pyridine, and 4.5 ml of piperidine was added. 80 this mixture
The mixture was stirred at ° C for 1.5 hours, and then heated under reflux for 4.5 hours. After cooling, the reaction mixture was poured into 1000 ml of ice water and concentrated hydrochloric acid 155 ml.
Acidify with, remove the precipitated crystals, and add 200 ml of water to 2
Washed twice. Next, the obtained crystals were dissolved in a 0.625N sodium hydroxide aqueous solution, and the insoluble matter was removed by excess. Liquid
It was diluted with 360 ml of water, 600 ml of 6N-hydrochloric acid aqueous solution was added to make it acidic, and the precipitated crystals were collected, washed twice with 200 ml of water and dried. 53.8 g (86%) of the title compound having a melting point of 182-183 ° C.
%)Obtained.

NMR (CDCl ₃ ) δ: 3.92 (6H, s), 6.33 (1H, d), 7.74 (1H,
d) Reference Example 2: (Z) -3,4-dimethoxycinnamic acid (E) -3,4-dimethoxycinnamic acid 20.0 g obtained in Reference Example 1
(96.1 mM) was added to 1,000 ml of water in which 10 g (94.3 mM) of sodium carbonate was dissolved, dissolved by heating, and cooled to room temperature. Next, this solution is used as a high pressure mercury lamp (USHIO UM452 type).
It was irradiated with light and subjected to photoreaction. The progress of the reaction was checked using HPLC, and the reaction reached equilibrium after 11 hours, so the reaction was stopped. 10 ml of concentrated hydrochloric acid was added to the reaction mixture, the precipitated crystals (mainly E form) were separated, and further concentrated hydrochloric acid was added to the liquid.
25 ml was added, and the precipitated crystals (E form was the main component) were separated. When 4.0 ml of concentrated hydrochloric acid was added to the obtained liquid, white crystals were precipitated, washed with cold water and dried to 8.41 g (Z / E = 97.1 /).
Crystals of 2.9) were obtained. Furthermore, 3.5 ml of concentrated hydrochloric acid was added to the solution, and 0.87 g (Z / E = 56.0 / 44.0) of crystals were obtained in the same manner. The yield of Z-form in the recrystallization was 43%.

NMR (CDCl ₃ ) δ: 3.89 (3H, s), 3.91 (3H, s), 5.85 (1H,
d), 6.84 (1H, d), 6.94 (1H, d), 7.21 (1H, d), 7.70 (1
H, s) Reference Example 3: (Z) -4-pentylcinnamic acid (Z) -3-pentylcinnamic acid 3.00 g (13.7 mM) was added to 3.00 g.
(28.3 mM) sodium carbonate was dissolved in 1,500 ml of water, and light irradiation was carried out in the same manner as in Reference Example 2. 2.92 g (Z / E = 93.5 / 6.5) of the desired title compound was obtained. The yield of Z-form was 91%.

NMR (CDCl ₃ ) δ: 0.89 (3H, s), 5.89 (1H, d), 6.99 (1H,
d), 7.16 (2H, d), 7.57 (2H, d) Example 1: 3-[(Z) -3,4-dimethoxycinnamoylamino] propionic acid (Z) -3, obtained in Reference Example 2 4-dimethoxycinnamic acid 2.00 g
(9.61mM) and isobutyl chloroformate 1.45g (10.6mM
M) was dissolved in 10 ml of dimethylformamide, and 1.07 g (10.6 mM) of triethylamine in 10 ml of dimethylformamide was added dropwise at -20 ° C. After stirring at the same temperature for 0.5 hour, 0.941 g (10.6 mM) of 3-aminopropionic acid was added at 0 ° C, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography using 60 g of silica gel (eluent: isopropyl ether: acetic acid = 3: 1 to 1: 1).
The product was purified in 1) and further treated with activated carbon to give the title compound as an oily substance (1.5 g, 56%).

Elemental analysis: Calculated: C: 60.21; H: 6.13; N: 5.01 Found: C: 59.70; H: 6.12; N: 4.92 NMR (CDCl ₃ ) δ: 2.53 (2H, d), 3.52 (2H, q ), 3.84 (6H,
s), 5.87 (1H, d), 6.40 (1H, br), 6.67 (1H, d), 6.7 ~
7.2 (3H, m), 9.0 ~ 9.1 (1H, br) IR (Nudior) cm ^-1 : 3340 (NH), 1710 (COOH), 1640
(CONH) Example 2: 3-[(Z) -4-pentylcinnamoylamino] propionic acid Using the (Z) -4-pentylcinnamic acid and 3-aminopropionic acid obtained in Reference Example 3, React as in 1.
The title compound was obtained as crystals with a melting point of 71-72 ° C. in a yield of 75%.

Elemental analysis: Calculated: C: 70.56; H: 8.01; N: 4.84 Found: C: 70.52; H: 8.00; N: 4.81 NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.30 (4H, m ), 1.60 (2H,
m), 2.5-2.6 (4H, m), 3.49 (2H, m), 6.14 (1H, m), 7.1
2 (2H, d), 7.33 (2H, d), 9.5-9.6 (1H, br) IR (Nudjol) cm ^-1 : 3350,1700,1640 Example 3: 2-[(Z) -3,4- Dimethoxycinnamoyloxy] benzoic acid 2.37 g of (Z) -3,4-dimethoxycinnamic acid obtained in Reference Example 2
(11.4mM) and isobutyl chloroformate 1.71g (12.5m
M) was dissolved in 8.7 ml of tetrahydrofuran, and a tetrahydrofuran solution of 2.55 g (25.0 mM) of triethylamine was added dropwise at -20 ° C. After stirring for 0.5 hours at the same temperature, 1.57 g (11.4 mM) of salicylic acid was added, and the mixture was stirred overnight at room temperature. Then, the reaction solution was made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-toluene-hexane to obtain 1.38 g (37%) of the title compound as crystals having a melting point of 140-142 ° C.

Elemental analysis: Calculated value: C: 65.85; H: 4.91 Found value: C: 65.85; H: 4.92 NMR (CDCl ₃ ) δ: 3.83 (3H, s), 3.85 (3H, s), 6.06 (1H,
d), 6.93 (1H, d), 6.7 to 8.1 (7H, m), 10.7 to 10.9 (1H, b
r) IR (nudhyol) cm ⁻¹ : 1730,1690 Example 4: 2-[(Z) -4-pentylcinnamoyloxy] benzoic acid (Z) -4-Pentylcinnamic acid and salicylic acid were used in Example 3. According to the method described, the title compound was obtained as crystals having a melting point of 145 to 147 ° C. Yield 25%.

Elemental analysis: Calculated value: C: 74.54; H: 6.55 Found value: C: 74.44; H: 6.25 NMR (CDCl ₃ ) δ; 0.86 (3H, t), 1.28 (4H, m), 1.57 (2H,
m), 2.56 (2H, t), 6.12 (1H, d), 7.02 (1H, d), 7.14 (2
H, d), 7.65 (2H, d), 7.1 to 8.1 (4H, m), 11.1 to 11.4 (1
H, br) IR (nudijol) cm ^-1 : 1730,1680 Example 5: N-[(Z) -3,4-dimethoxycinnamoyl]
-2- (tetrazol-5-yl) aniline (A) (Z) -3,4-dimethoxycinnamic acid 4.0 g (19.2 m
M), isobutyl chloroformate 2,88 g (21.1 mM) and anthranilonitrile 2.49 g (21.1 mM) were used, Example 1
And N-[(Z) -3,4-dimethoxycinnamoyl] anthranilonitrile having a melting point of 138 to 139 ° C.
To obtain 1.59 g (27%) of crystals.

NMR (CDCl ₃ ) δ: 3.80 (3H, s), 3.89 (3H, s), 6.01 (1H,
d), 6.92 (1H, d), 6.8 to 8.5 (7H, m), 7.74 (1H, br) (B) Then, the compound obtained in the above (A) 2.30 g (7.46m)
M), sodium azide 0.533 g (8.21 mM) and ammonium chloride 0.439 g (8.21 mM) in dimethylformamide 1
It was dissolved in 1.5 ml and stirred at 120 ° C. for 2 hours. After completion of the reaction, the reaction solution is poured into ice water and acidified with dilute hydrochloric acid to precipitate crystals. After collection, washing with water and drying, the product was purified by column chromatography using 30 g of silica gel (eluent: hexane: ethyl acetate = 7: 3 to 5: 5) and crystallized with an ether-hexane mixture, melting point 148 0.235g as crystals at ~ 150 ℃
(9.0%) obtained.

Elemental analysis: Calculated value: C: 61.52; H: 4.88; N: 19.93 Found value: C: 61.09; H: 4.86; N: 19.67 NMR (CD ₃ OD) δ: 3.36 (3H, s), 3.61 (3H, s), 6.07 (1H,
d), 6.7 to 8.6 (8H, m), 11.18 (1H, s) IR (nudijol) cm ^-1 : 3200,1670 Example 6: 3-acetoxy-1-[(Z) -3,4-dimethoxycinna Moyl] indole (Z) -3,4-dimethoxycinnamic acid 5.40 g (25.9 mM) and isobutyl chloroformate 3.89 g (28.5 mM) were dissolved in 25 ml of dimethylformamide, and triethylamine 2.
A solution of 88 g of 25 ml of dimethylformamide was added dropwise. After stirring at the same temperature for 0.5 hours, 3-acetoxyindole 4.99 g
(28.5mM) and dimethylaminopyridine 50mg (0.41m
M) was added. After that, the mixture was heated to 40 ° C., stirred overnight at the same temperature, the reaction solution was poured into ice water and extracted with ethyl acetate.
The extract was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography using 250 g of silica gel (eluent: hexane: ethyl acetate = 2:
Purified in 1), crystallized from methanol, melting point 86-87 ℃
As a crystal, the title compound (1.35 g, 14%) was obtained.

Elemental analysis: Calculated: C: 69.03; H: 5.24; N: 3.83 Found: C: 68.87; H: 5.22; N: 3.80 NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.60 (3H, s) ), 3.81 (3H,
s), 6.30 (1H, d), 6.91 (1H, d), 6.7 to 8.6 (7H, m), 7.7
3 (1H, s) IR (nudhyol) cm ⁻¹ : 1750,1660 Example 7: 3-acetoxy-1-[(Z) -4-pentylcinnamoyl] indole (Z) -4-pentylcinnamic acid and 3 -Using acetoxyindole, the reaction was performed in the same manner as in Example 6 to obtain the title compound in a yield of 4.9%.

NMR (CDCl ₃ ) δ: 0.86 (3H, t), 1.26 (4H, m), 1.55 (2H,
m), 2.33 (3H, s), 2.53 (2H, t), 6.38 (1H, d), 6.97 (1
H, d), 7.07 (2H, d), 7.38 (2H, d), 7.75 (1H, s), 7.2 ~
7.6 (4H, m) Example 8: 1-[(Z) -3,4-dimethoxycinnamoyl]
-3-Hydroxyindole 0.644 g (1.76 mM) of the compound obtained in Example 6 was added to methanol.
It was dissolved in 40 ml, and several drops of sodium methylate were added dropwise at room temperature, followed by stirring at the same temperature for 0.5 hours. Neutralize the reaction solution,
The mixture was dried under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, the residue was crystallized with methanol, and further purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1), crystallized with methanol, and crystals with a melting point of 92-93 ° C. As a title compound 0.250 g (44
%)Obtained.

Elemental analysis: Calculated: C: 70.59; H: 5.30; N: 4.33 Found: C: 69.64; H: 5.32; N: 4.26 NMR (CDCl ₃ ) δ: 3.70 (3H, s), 3.83 (3H, s) ), 4.11 (2H,
s), 6.05 (1H, s), 7.03 (1H, d), 6.7 to 7.7 (7H, m) IR (nudijol) cm ^-1 : 1710,1650 Example 9: 1-[(Z) -4-pentyl Cinnamoyl]-
3-Hydroxyindole The compound obtained in Example 7 was reacted in the same manner as in Example 8,
Obtained as crystals with a melting point of 69 to 70 ° C. in a yield of 55%.

Elemental analysis: Calculated: C: 79.26; H: 6.95; N: 4.20 Found: C: 79.00; H: 6.93; N: 4.18 NMR (CDCl ₃ ) δ: 0.86 (3H, t), 1.27 (4H, m ), 1.56 (2H,
m), 2.54 (2H, t), 4.12 (2H, s), 6.11 (1H, d), 6.82 (1
H, d), 7.10 (2H, d), 7.38 (2H, d), 7.2 to 8.4 (4H, m) IR (Nudior) cm ^-1 : 1720,1670 Example 10: N-[(Z) -4 -Pentylcinnamoyl] anthranilic acid (Z) -4-Pentylcinnamic acid and anthranilic acid were used and reacted in the same manner as in Example 1 to obtain crystals with a melting point of 109 to 110 ° C as a yield of 96%.

Elemental analysis: Calculated: C: 74.76; H: 6.87; N: 4.15 Found: C: 74.31; H: 6.82; N: 4.15 NMR (CDCl ₃ ) δ: 0.84 (3H, t), 1.2-1.3 (4H , m), 1.45
~ 1.55 (2H, m), 2.52 (2H, t), 6.07 (1H, d), 6.89 (1H,
d), 7.08 (2H, d), 7.46 (2H, d), 7.0 ~ 8.9 (4H, m), 9.5
~ 9.7 (1H, br), 10.83 (1H, s) IR (nudhyol) cm ^-1 : 3330,1690,1660 Example 11: N-[(Z) -4-pentylcinnamoyl] anthranilic acid (Z)- 4-Pentylcinnamic acid was reacted in the same manner as in Example 10 to obtain crystals with a melting point of 173-174 ° C in a yield of 56%.

Elemental analysis: Calculated value: C: 74.76; H: 6.87; N: 4.15 Found value: C: 74.59; H: 6.84; N: 4.13 NMR (CDCl ₃ ) δ: 0.89 (3H, t), 1.25 to 1.35 (4H , m), 1.5
5 to 1.65 (2H, m), 2.59 (2H, t), 6.60 (1H, d), 7.18 (1
H, d), 7.49 (1H, d), 7.81 (1H, d), 7.0 to 9.0 (4H, m), 1
0.33 (1H, s), 11.1 to 11.2 (1H, br) IR (Nudior) cm ⁻¹ : 3150,1680,1650 Example 12: N- [2- (3,4-dimethoxyphenyl) cyclohexylcarbonyl] anthranyl Production of acid (A) 1-[(E) -1,3-butadienyl] -3,4-dimethoxybenzene Allyltriphenylphosphonium bromide 50.6 g (132 m
M) in 250 ml of toluene, cooled with ice under a nitrogen atmosphere, and 846 ml of 10% butyllithium-hexane solution (132 mM).
Was dripped. Then, stir at room temperature for 1 hour, then -50
The mixture was cooled to ° C, and a toluene solution of 2,4-dimethoxybenzaldehyde (20.2 g, 120 mM) was added dropwise at the same temperature. After stirring at the same temperature for 0.5 hour, the insoluble matter in the reaction mixture was separated and washed with 250 ml of hexane. The solution and the washing solution were poured into ice water, the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was concentrated, and the obtained triphenylphosphinioxide was separated and purified by column chromatography using 1160 g of silica gel (eluent: hexane: isopropyl ether = 3: 1) to obtain 5.3 g of the title compound. .

NMR (CDCl ₃ ) δ: 3.87 (3H, s), 3.90 (3H, s), 5.12 (1H,
d), 5.29 (1H, d), 6.6 to 7.0 (6H, m) (B) Production of methyl 2- (3,4-dimethoxyphenyl) -3-cyclohexenecarboxylate Compound obtained in step (A) above 5.76 g and methyl acrylate 17.2 g were dissolved in 120 ml of benzene, 408 mg of aluminum chloride was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Column chromatography using 640 g of silica gel (eluent: hexane: isopropyl ether = 1: 3)
The title compound was obtained as crystals with a melting point of 112-113 ° C.

_{NMR (CDCl 3) δ: 1.62~1.75} (2H, m), 2.1~2.4 (3H,
m), 2.85 to 2.95 (1H, m), 3.51 (3H, s), 3.85 (6H, s),
5.7 to 5.8 (1H, m), 5.9 to 6.0 (1H, m), 6.7 to 6.8 (3H, m) (C) Production of 2- (3,4-dimethoxyphenyl) cyclohexanecarboxylic acid The above step (B) 1.9 g of the compound obtained in 1. was subjected to catalytic reduction with platinum oxide in 50 ml of a solution of ethanol-ethyl acetate 2: 3 and treated in a conventional manner to give 1.7 g of the methyl ester of the title compound. NMR (CDCl ₃ ) δ: 3.84 (3H, s), 3.85 (3
H, s), 6.77 (3H, s). This methyl ester was then
-Sodium hydroxide-ethanol solution 32 ml and water 0.58
It was dissolved in ml and heated under reflux for 2 hours for hydrolysis. After completion of the reaction, the reaction solution was concentrated, water was added and the mixture was washed with chloroform, the aqueous layer was adjusted to pH 3.0 with dilute hydrochloric acid, extracted with ethyl acetate, and treated by a conventional method to obtain 1.25 g (89%) of the title compound. .

NMR (CDCl ₃ ) δ: 1.0 to 3.0 (10H, m), 3.83 (6H, s), 6.65
-6.8 (3H, m) (D) Production of N- [2- (3,4-dimethoxyphenyl) cyclohexylcarbonyl] anthranilic acid 1.09 g of the carvone obtained in the above step (C) was replaced with 20 m of thionyl chloride.
It was dissolved in 1 and heated to reflux for 4 hours. The reaction solution was dried under reduced pressure, the residue was dissolved in 15 ml of tetrahydrofuran, and 685 mg of methyl anthranilate was added. Then, 917 mg of triethylamine was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated and then purified by silica gel column chromatography (eluent: hexane: isopropyl ether = 1: 3) to obtain 840 mg of the methyl ester of the title compound. NMR
(CDCl ₃ ) δ: 3.75 (3H, s), 3.82 (3H, s), 3.89 (3H,
s). Then, using 680 mg of this ester, the same hydrolysis reaction as in step (B) was carried out, and the mixture was treated in a conventional manner to give 581 m of the title compound.
g (89%) was obtained as crystals with a melting point of 176-177 ° C.

NMR (CDCl ₃ ) δ: 1.4-3.0 (10H, m), 3.69 (3H, s), 3.76
(3H, s), 6.0 ~ 7.0 (5H, m), 7.42 (1H, t), 7.9 ~ 8.0 (1
H, m), 8.4 to 8.6 (1H, m), 11.0 to 12.0 (1H, br) IR (nudijol) cm ^-1 : 3330,1690,1670 Example 13: N- [2- (4-pentylphenyl) ) Cyclohexylcarbonyl] anthranilic acid It is produced by reacting 4-pentylbenzaldehyde in the same manner as in Steps A to D of Example 12. The compounds obtained in each step and their characteristics are as follows.

1-[(E) -1,3-butadienyl] -4-pentylbenzene NMR (CDCl ₃ ) δ: 0.89 (3H, t), 1.3 to 1.4 (2H, m), 1.55
~ 1.65 (4H, m), 2.59 (2H, t), 5.19 (1H, d), 5.34 (1H,
d), 6.21 (1H, t), 6.42 (1H, d), 6.85 ~ 6.95 (1H, m),
7.14 (2H, d), 7.23 (2H, d) 2- (4-Pentylphenyl) -3-cyclohexenecarboxylate methyl NMR (CDCl ₃ ) δ: 0.89 (3H, t), 3.47 (3H, s) 2 Methyl-(4-pentylphenyl) -3-cyclohexanecarboxylate NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.25 to 1.35 (4H, m), 2.4
~ 3.15 (9H, m), 2.2 ~ 2.5 (1H, m), 2.55 (2H, t), 2.8 ~
3.0 (2H, m), 3.41 (3H, s), 7.10 (4H, d) 2- (4-pentylphenyl) cyclohexanecarboxylate methyl NMR (CDCl ₃ ) δ: 0.88 (3H, t), 1.2-3.0 (16H, m), 2.54
(2H, t), 7.06 (4H, s), 8.5-9.5 (1H, br) Methyl N- [2- (4-pentylphenyl) cyclohexylcarbonyl] anthranilate NMR (CD ₃ OD) δ: 0.80 (3H , t), 1.0 to 2.9 (10H, m), 3.87
(3H, s), 6.62 (1H, s), 6.8 to 7.2 (5H, m), 7.35 to 7.4
(1H, m), 7.85 to 7.9 (1H, m), 8.2 to 8.3 (1H, m) N- [2- (4-pentylphenyl) cyclohexylcarbonyl] anthranilic acid Melting point: 108 to 109 ° C NMR (CDCl ₃ ) Δ: 0.82 (3H, t), 1.0 to 4.0 (18H, m), 6.99
(2H, d), 7.15 (2H, d), 6.8 to 7.2 (1H, m), 7.47 (1H,
t), 8.05 (1H, d), 8.53 (1H, d), 10.5 to 11.0 (1H, br) IR (nudijol) cm ^-1 : 3350,1690,1660 Example 14: N- (3-bromo-4 , 5-Dimethoxyphenylpropioroyl) anthranilic acid 3-Bromo-4,5-dimethoxyphenylpropiolic acid
To a solution of 2.85 g and 1.09 g of ethyl chlorocarbonate in 15 ml of tetrahydrofuran, a solution of 2.02 g of triethylamine in 3 ml of tetrahydrofuran was added dropwise at 0 ° C. over 0.5 hour. Then, a solution of 1.37 g of anthranilic acid in 4 ml of tetrahydrofuran was added dropwise at 0 ° C. for 0.5 hours, and then stirred at 20 ° C. for 3 hours. After the completion of the reaction, the mixture was treated by a conventional method to give 2.27 g of the title compound as crystals having a melting point of 240 ° C.

NMR (DMSO-d ₆ ) δ: 3.82 (3H, s), 3.86 (3H, s), 7.08-
7.40 (3H, m), 7.66 (1H, t), 8.03 (1H, d), 8.46 (1H,
d) IR (nudijol) cm ^-1 : 3300,2200,1660 Example 15: N-[(Z) -3-Bromo-4,5-dimethoxycinnamoyl] anthranilic acid 2.01 g of the compound obtained in Example 14 , 0.1% quinoline and 50 ml methanol in suspension, 5% palladium-barium sulfate
40 mg was subjected to catalytic reduction, and after absorbing a theoretical amount of hydrogen, the catalyst was separated and the reaction solution was concentrated. The residue was treated with aqueous sodium carbonate solution-ethyl acetate, the aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was evaporated. The residue was recrystallized from a 3% water-methanol mixture to give the title compound (0.5) as crystals with a melting point of 186 ° C.
2g was obtained.

NMR (DMSO-d ₆ ) δ: 3.57 (3H, s), 3.77 (3H, s), 6.06
(1H, d), 6.90 (1H, d), 6.85 to 8.15 (5H, m), 8.60 (1H,
m), 11.5 (1H, br) IR (nudijol) cm ^-1 : 3350,1705,1695,1615 Example 16: N- (4-chlorophenylpropioloyl) anthranilic acid 4-chlorophenylpropiolic acid is used Example 14
The title compound was obtained as crystals with a melting point of 203.7 ° C.

IR (nudjiol) cm ^-1 : 3300,2250,2200,1690,1670 Example 17: N- [2- (3,4-dimethoxyphenyl) -4,5
-Dimethyl-4-cyclohexenoyl] anthranilic acid (A) Dissolve 1 g of 3,4-dimethoxycinnamic acid and 5 ml of 2,3-dimethyl-1,3-butadiene in 40 ml of benzene, add 40 mg of aluminum chloride and reflux for 10 hours. did. After completion of the reaction, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: hexane: tetrahydrofuran = 6: 1) to give 2- (3,4-dimethoxyphenyl) -4. 5,5-Dimethyl-4-cyclohexenecarboxylic acid was obtained.

NMR (CDCl ₃ ) δ: 1.63 (6H, s), 2.2 (4H, m), 2.87 (2H,
m), 3.82 (6H, s), 6.65 (3H, m) IR (nudhyol) cm ^-1 : 1700 (B) Using the carboxylic acid and methyl anthranilate obtained in the above step (A), the same as Example 1. Processed, N-
Methyl [2- (3,4-dimethoxyphenyl) -4,5-dimethoxy-4-cyclohexenoyl] anthranilate was obtained.

NMR (CDCl ₃ ) δ: 1.65 (6H, s), 3.7 (3H, s), 3.8 (3H,
s), 3.86 (3H, s) IR (nudhyol) cm ^-1 : 1680 (C) The methyl ester obtained in step (B) was hydrolyzed with a 10% aqueous sodium hydroxide solution and treated in a conventional manner to give the title compound. Obtained as crystals with a melting point of 200-201 ° C.

NMR (CDCl ₃ ) δ: 1.64 (6H, s), 3.73 (3H, s), 3.78 (3H,
s) IR (nudijol) cm ^-1 : 1680 Example 18: N- [2- (3,4-dimethoxyphenyl) -3
-Cyclohexenoyl] anthranilic acid Using methyl 2- (3,4-dimethoxyphenyl) -3-cyclohexenecarboxylate obtained in step (B) in Example 12, it was hydrolyzed to form a carboxylic acid, and then anthranilic acid. The same procedure as in step (D) of Example 12 could be performed using methyl. The compound produced in each step and its physical properties are as follows.

2- (3,4-dimethoxyphenyl) -3-cyclohexenecarboxylic acid NMR (CDCl ₃ ) δ: 1.98 (1H, m), 2.14 (1H, m), 2.58 (1H,
m), 3.7 (1H, m), 3.81 (3H, m), 3.83 (3H, m) IR (Nudior) cm ^-1 : 1700 N- (2- (3,4-dimethoxyphenyl) -3-cyclohexyl Cenoyl] methyl anthranilate NMR (CDCl ₃ ) δ: 1.7 to 2.5 (3H, m), 3.73 (3H, s), 3.75
(3H, s), 3.66 (3H, s), 3.82 (3H, s) IR (nudhyol) cm ⁻¹ : 1700,1680 N- (2- (3,4-dimethoxyphenyl) -3-cyclohexenoyl ] Anthranilic acid NMR (CDCl ₃ ) δ: 2.0-2.6 (3H, m), 4.73 (1H, m), 4.74
(3H, s), 4.76 (3H, s), 5.63 to 6.0 (2H, m), 6.74 (3H,
m) IR (Nujiorum cm ^-1 : 1680

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP 49-93335 (JP, A) JP 50-135047 (JP, A) JP 58-8046 (JP, A)

Claims (1)

[Claims] 1. A general formula (I) In the formula, R ¹ and R ² each represent an alkoxy group, or one represents an alkyl group and the other represents a hydrogen atom; Y is a 3- (hydroxy or acetoxy) indol-1-yl group, carboxyalkyleneamino Basis or Wherein R ⁶ represents a tetrazolyl group, and a compound or salt thereof.