JPS5830302B2 - Shinki Hōkōzoku Carbon Sanamide Yudōtai no Seizō Hōhō - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel aromatic carboxylic acid amide derivative having pharmacological effects.

More specifically, the present invention relates to a method for producing an N-substituted amide of cinnamic acid or hydrocinnamic acid having a branched or unsaturated substituent group in the nucleus, which is useful as a therapeutic agent for diseases caused by allergies. It is something.

Until now, zincium cromoglycate has been known as an anti-allergic agent that suppresses the release of chemical mediators caused by antigen-antibody reactions, but this drug has no medicinal effect at all when administered orally. Therefore, its scope of use was naturally limited.

Therefore, the development of antiallergic agents that exhibit sufficient therapeutic effects even when administered orally has become an important issue in this field.

As a result of various studies aimed at achieving the above object, the present inventors have found that certain aromatic carboxylic acid amide derivatives have excellent anti-allergic effects and are also sufficiently effective when administered orally. Heading, first the general formula (R in the formula is a linear lower alkyl or alkoxy group,
R1 and R2 are each a hydrogen atom or a lower alkyl group,
R3 and R4 are each a hydrogen atom, or both form a chemical bond).

However, as a result of further research in order to further enhance this pharmacological effect, it was found that the nuclear substituent corresponding to R in the above general formula was replaced with a branched lower alkyl group, a branched lower alkoxy group,
By using a linear or branched lower alkenyl group or a linear or branched lower alkenyloxy group,
We have discovered that scales have significantly enhanced anti-allergic effects.

The sixth aspect of the present invention has been made based on this knowledge.

That is, according to the present invention, the general formula (in which R1 and R2 are each a hydrogen atom or a lower alkyl group, R3 and R4 are each a hydrogen atom or both form a chemical bond, and at least One is a branched lower alkyl group, a branched lower alkoxy group, a linear or branched lower alkenyl group, or a linear or branched lower alkenyloxy group; the others are hydrogen atoms, hydroxyl groups, or linear (lower alkoxy group, n is an integer of 1 or 2) is reacted with aminobenzoic acid or its ester represented by the general formula, and if necessary hydrated. By decomposition and converting the nuclear substituted ester group into a free carboxyl group and optionally converting the product into a salt, the general formula (wherein R1, R2, R3, R4+X and n have the same meanings as above) An aromatic carboxylic acid amide derivative or a salt thereof can be produced.

The aromatic carboxylic acid represented by the general formula (I) is a known compound and can be easily produced according to methods described in literature.

In the case of a compound in which R3 and R4 form a chemical bond, that is, a nuclear-substituted cinnamic acid or a derivative thereof, there are cis and trans isomers, both of which can be used in the present invention.

Examples of the aromatic carboxylic acid of general formula (I) include 4-isopropylhydrocinnamic acid, 2-. 3- or 4-allyloxyhydrocinnamic acid, 2-. 3- or 4-methallyloxyhydrocinnamic acid, 2-23-2 or 4-impropoxyhydrocinnamic acid, 2-. 3-, or 4-imbutoxyhydrocinnamic acid, 2-93-9 or 4-sec-butoxyhydrocinnamic acid, 3-methoxy-4-impropoxyhydrocinnamic acid, 2-impropoxy-4-methoxy Hydrocinnamic acid, 3-inpropoxy-4methoxyhydrocinnamic acid, 4-allyloxy-3methoxyhydrocinnamic acid, 2-allyloxy-3methoxyhydrocinnamic acid, 3
-Allyloxy-4-methoxyhydrocinnamic acid, 4-methacroxy-3-methoxyhydrocinnamic acid, 2-metasoroxy-3-methoxyhydrocinnamic acid, 3-metasoroxy-
4-methoxyhydrocinnamic acid, 4-imbutoxy-3-
Methoxyhydrocinnamic acid, 4-sec-butoxy-3-methoxyhydrocinnamic acid, 3,4-diallyloxyhydrocinnamic acid, 3,4-dimethryloxyhydrocinnamic acid, and the above hydrocinnamic acids. α- or β-alkyl-substituted aromatic saturated carboxylic acids having the same substituents as 4-isopropylcinnamic acid, 2-. 3'-t or 4-aryloxycinnamic acid, 2-. 3- or 4-allyloxycinnamic acid, 2-. 3- or 4-impropoxycinnamic acid, 2-. 3- or 4-imbutoxycinnamic acid, 2-
23- or 4-sec-butoxycinnamic acid, 3-methoxy-4-impropoxycinnamic acid, 2-impropoxy-
4-methoxycinnamic acid, 3-isopropoquine-4-methoxycinnamic acid, 4-allyloxy-3-methoxycinnamic acid, 2-allyloxy-3-methoxycinnamic acid, 3-allyloxy-4-methoxycinnamic acid , 4-Mecryloxy-3-methoxycinnamic acid, 2-Mecryloxy-3-methoxycinnamic acid, 3-Methasoloxy-4-methoxycinnamic acid, 4-
Isobutoxy-3-methoxycinnamic acid, 4-sec-butoxy-3-methoxycinnamic acid, 3,4-diallyloxycinnamic acid, 3,4-dimethallyloxycinnamic acid, 3-allyl-
Mention may be made of 4-hydroxycinnamic acid and α- or β-alkyl-substituted aromatic unsaturated carboxylic acids having the same substituents as mentioned above.

In the process of the present invention, reactive functional derivatives of these aromatic carboxylic acids are used as starting materials, including carboxylic acid derivatives such as acid halides, acid anhydrides, mixed acid anhydrides, and esters. I can give you something.

These reactive functional derivatives can be prepared using the general formula (1
) can be easily derived from aromatic carboxylic acids.

For example, acid halides can be easily obtained by heating an aromatic carboxylic acid and an acid halogenating agent such as thionyl chloride for several hours without a solvent or in a suitable organic solvent.

Further, mixed acid anhydrides can be obtained, for example, by reaction with chloroformate or sulfonic acid halide.

This reactive functional derivative may be isolated once from the reaction system, or may be continuously reacted with the aminobenzoic acid of general formula (II) or its ester without being isolated.

Aminobenzoic acid of general formula (II) is anthranilic acid, 3
-Aminobenzoic acid or 4-aminobenzoic acid may be used.

Moreover, instead of this aminobenzoic acid, an ester represented by the general formula (R5 in the formula is a hydrocarbon group, a substituted hydrocarbon group, or a cyclic hydrocarbon group which may be interrupted by a different atom) may be used. You can also do it.

Examples of the ester of general formula (II') include methyl ester, ethyl ester, furoyl ester, chloroethyl ester, hydroxyethyl ester, benzyl ester, cyclohexyl ester, and tetrahydropyranyl ester, which can be prepared in a conventional manner. It can be easily converted into a free carboxyl group by hydrolysis.

The amidation reaction in the present invention can be carried out according to a method known per se.

For example, when using an acid halide as the reactive derivative, the two can be reacted in the presence of a basic substance in an inert solvent.

In this case, the basic substances include triethylamine, pyridine, 2-. 3-y or 4-methylpyridine, N, N-
Organic bases such as dimethylaniline, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate are used.

Further, as the inert solvent, chloroform, methylene chloride, acetone, benzene, toluene, tetrahydrofuran, dioxane, water, and mixtures thereof can be used.

Instead of using the above-mentioned basic substance, the compound of general formula (II) may be used in an excess amount, that is, twice or more moles relative to the compound of general formula (I), for the reaction.

To suitably carry out the method of the present invention, the compound of general formula (4) is dissolved in a mixed solution of 5 to 20 times the amount of chloroform and 2 to 15 times the amount of pyridine based on the compound of general formula (I), A chloroform solution of the reactive functional derivative of the compound of general formula (1) is cooled and added dropwise to this solution with stirring, followed by heating for several hours if necessary.

The reaction product is concentrated under reduced pressure, and the residue is hydrolyzed, if necessary, with an aqueous solution of sulfur hydroxide, and then made weakly acidic by adding hydrochloric acid.

Take the precipitated crystals and recrystallize them from a suitable solvent to obtain the desired product.

In the above general formula (III), a compound in which R3 and R4 are hydrogen atoms, that is, a compound represented by the general formula (R, , R2, X and n in the formula have the same meanings as above), has the corresponding substitution Hydrocinnamic acid having a group can be easily obtained as a starting material.

The aromatic amide compound formed by the condensation reaction as described above can be converted into a pharmacologically acceptable salt form according to a conventional method, if desired.

For example, the compound of general formula (1) is made into an alcohol solution,
A sodium salt can be obtained by adding an aqueous solution containing an equivalent amount of sodium hydroxide and heating for an appropriate time as required.

The aromatic amide derivatives obtained by the present invention effectively act on symptoms caused by antigen-antibody reactions, and are therefore useful as therapeutic agents for diseases based on allergies.

Next, the present invention will be explained in more detail with reference to Examples.

Note that the melting points of the products in each example are uncorrected.

Example 1 Preparation of 2-(3'-methoxy-4'-isopropoxycinnamoylamino)benzoic acid 2.5 g of 3-methoxy-4-impropoxycinnamic acid is refluxed for 2 hours in 5 g of thionyl chloride and 30 ml of benzene. .

Concentrate under reduced pressure to obtain the acid chloride.

2 g of anthranilic acid to 1.6 g of pyridine. Dissolve in a mixture of @ and 30 ml of chloroform, cool, and dropwise add the acid chloride solution in chloroform while stirring.

After dropping, heat to 50-60°C for 2 hours. The reaction solution is concentrated under reduced pressure and the residue is poured into ice water and then acidified with hydrochloric acid.

The precipitated crystals were taken, recrystallized from hydroalcohol, and 2-
2.2 g of (3'-methoxy-4'-impropoxycinnamoylamino)benzoic acid are obtained.

The melting point is 76-78°co.The properties of this product are as follows.

Infrared absorption spectrum (KBr) νCO1685cm, -1,1660m' Elemental analysis value CHN as C2oH2,05N Calculated value 67.59 5.96 3.94 Actual value
67.39 5,82 3.63 Nuclear magnetic resonance spectrum (CD3COCD3,90MH2) δ1.3 (d, 6
H, impropoxy group methyl hydrogen) 3.9 (S, 3H
・Methyl hydrogen of methoxy group) 4.6 (g, IH・Methyl hydrogen of impropoxy group) 6.65, 7.62 (g・2H-J216Hz・olefin hydrogen) 7.0~
77 (broad, IH, amide hydrogen) 11.3
(S, IH, carboxylic acid hydrogen) 6.9-9.
0 (m, 7H, aromatic ring hydrogen) 1.775 g of 2-(3'-methoxy-4'isopropoxycinnamoylamino)benzoic acid obtained as above was dissolved in 20 ml of ethanol, and 0.2 g was dissolved in this. hydroxide of sl-IJ
Dissolve um in 5TLl of water, add this aqueous solution, and add 30
Warm for a minute.

Next, the reaction solution was concentrated, the precipitated crystals were dissolved in ethanol, an appropriate amount of isopropyl ether was added thereto, and the mixture was left to cool. 1.4 g of the sodium salt of cinnamoylaminobenzoic acid are obtained.

Melting point 300℃ or higher.

Example 2 Production of 2-(4'-isopropylcinnamoylamine)benzoic acid 4-isopropylcinnamic acid 3.8gf pyridine 20TI
Dissolve in Ll, cool, and dropwise add a solution of 3.6 g of benzenesulfonic acid chloride in pyridine to the solution while stirring.

After the addition was completed, the mixture was stirred at room temperature for 2 hours, and then a pyridine solution of 2.759 methyl γ-anthranilate was added dropwise.

After completion of dropping, heat to 80-100°C for 1.5 hours.

After the reaction is completed, the reaction solution is concentrated, the residue is poured into ice water, and acidified with hydrochloric acid.

This solution is extracted with chloroform, washed with water, extracted with a saturated solution of sodium bicarbonate, and then the chloroform layer is washed with water and concentrated under reduced pressure.

Dissolve the residue in an appropriate amount of alcohol, add an appropriate amount of 10% aqueous sodium hydroxide solution, and heat to hydrolyze.

After cooling, acidify with hydrochloric acid to precipitate crystals.

The precipitated crystals were collected and recrystallized from isopropyl ether to obtain 1.6 g of 2-(4'-isopropylcinnamoylamino)benzoic acid.

Melting point: 153-156° Co. Properties of this material are as follows.

Infrared absorption spectrum (KBr) vco 1690cIrL', 1660Crn-'
NH3300-1 Elemental analysis value C19HI903N CHN Calculated value 73.76 6.19 4.53 Actual value
74,02 6.23 4.2 Nuclear magnetic resonance spectrum (
CD3COCD3.90MHz) δ1.25 (d, 6
H, methyl hydrogen of isopropyl group) 3.0 (g, l
H, methyl hydrogen of isopropyl group) 6.75, 7.70
(g, 2H, olefin hydrogen) 7.05-9.0
(m-7H, aromatic ring hydrogen) 11.4 (S, IH
, hydrogen carboxylate) 2-(4'-
1.5 g of isopropylcinnamoylamino)benzoic acid was dissolved in 20 yrtl of ethanol, and an aqueous solution of 0.2 g of sodium hydroxide dissolved in 5 ml of water was added thereto.
Warm for 0 minutes.

Next, the reaction solution was concentrated, and the precipitated crystals were heated and dissolved in ethanol. An appropriate amount of isopropyl ether was added to this, and the mixture was left to cool. The precipitated crystals were taken out and dried, resulting in 2-(
1.4 g of the sodium salt of 4'-isopropylcinnamoylamino)benzoic acid are obtained.

Melting point: 198-205°C. The following compounds can be produced by similar operations.

Reference Example Rat homologous passive skin reagin-like antibody of Huanaphylaxis rat was treated with dinitrophenol-ascaris (D
NP-Ascaris) and in rats immunized with pertussis vaccine.

Normal rats were passively injected with a diluted rat reagin-like antibody to sensitize them.

After 48 hours, antigen (DNP-Ascaris) and dye Evansbourg are injected intravenously.

The rats were sacrificed 30 minutes after the antigen challenge, the skin was peeled off, and the degree of skin reaction caused by the release of the chemical mediator was measured by the amount of dye leaked.

The test compound is dissolved in 1% sodium bicarbonate solution and administered orally at 200 my/kg 2 hours before antigen challenge.

Three rats were used for one test compound.

Compounds for comparison of medicinal efficacy were 2- (4'-n-propoxycinnamoylamino)benzoic acid (melting point 165-168°C) 2- (4'-n-propylcinnamoylamino)benzoic acid (melting point 137-140°C) 2- Control using (3'methoxy-4'-n-propoxycinnamoylamino)benzoic acid (melting point 172-177°C) 2-(4'-n-butoxycinnamoylamino)benzoic acid (melting point 184-6°C) A 1% sodium bicarbonate solution was used.

The inhibition rate was calculated by the following formula.

Claims (1)

[Claims] (In the formula, R1 and R2 are each a hydrogen atom or a lower alkyl group, R3 and R4 are each a hydrogen atom or both form a chemical bond, and at least one of A branched lower alkyl group, a branched lower alkoxy group, a straight-chain or branched lower alkenyl group, or a straight-chain or branched lower alkenyloxy group, and the others are hydrogen atoms, hydroxyl groups, or straight-chain lower alkoxy groups. and n is an integer of 1 or 2) with an amine benzoic acid of the general formula and optionally converting the product into a salt. A method for producing an aromatic carboxylic acid amide derivative or a salt thereof represented by the formula -# (in which R, , R2+ R3, R4, X and n have the same meanings as above), characterized by: 2 general formula (in the formula, R1 and R2 are each a hydrogen atom or a lower alkyl group, R3 and R4 are each a hydrogen atom or both form a chemical bond, and at least one of X is a branched A lower alkyl group, a branched lower alkoxy group, a linear or branched lower alkenyl group, or a linear or branched lower alkenyloxy group, and the others are hydrogen atoms, hydroxyl groups, or linear lower alkoxy groups, n is an integer of 1 or 2) and the general formula (wherein R5 may be interrupted by a hydrocarbon group, a substituted hydrocarbon group or a heteroatom) It is characterized by reacting with an aminobenzoic acid ester represented by a certain cyclic hydrocarbon group, followed by hydrolysis to convert the nuclear-substituted ester group into a carboxyl group, and further converting the product into a salt as desired. A method for producing an aromatic carboxylic acid amide derivative or a salt thereof represented by the general formula (in which R1, R2, R3, R4, X and n have the same meanings as above).