JPS60146856A - Alpha-haloaromatic amidocarboxylic acid derivative and antiallergic comprising it - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (Y is OH, lower acyloxy, or lower alkoxyl; R<1> is OH, lower acyloxy, or lower alkoxyl; R<2> is H, or lower alkyl; X is halogen). EXAMPLE:2-Bromo-N-( 2-carboxyphenyl )-3-( 3,4-dimethoxyphenyl )-3-hydroxypropionamide. USE:An antiallergic. Showing improved inhibitory activity against 5-lipoxygenase. PREPARATION:An aromatic amidocarboxylic acid derivative shown by the formula II is reacted with a halogenating agent such as bromine, chlorine, etc. to give a compound shown by the formula III (X' is halogen). This compound is then treated with water, methanol, sodium acetate, etc. at room temperature - under heating, a halogen at beta-position is replaced with OH, lower acyloxy, or lower alkoxyl, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION Regarding acid derivatives and anti-allergic agents made of these compounds, more specifically, the general formula (Y in the formula may be the same or different).

hydroxyl group, lower acyloxy group or lower alkoxyl group, respectively %R1 is a hydroxyl group, lower acyloxy group or lower alkoxyl group, R2 is a hydrogen atom or a lower alkyl group,
X is a halogen atom) or a pharmaceutically acceptable salt thereof; The present invention relates to an antiallergic agent consisting of:

In recent years, chemical mediators (like histamine and serotonin) have become important in the fields of allergy and inflammation.
chemical mediator), SRS-A (slow reacting s
ubstance □fanaphylaxis) has been attracting attention. SRS-A is released in the lungs of sensitized guinea pigs and asthma patients, and is a substance that strongly contracts smooth muscles in the bronchi and intestinal tract, and plays an important role in atopic asthma and immediate allergic reactions. It is believed that this will be achieved.

The SRI3-A has arachidonic acid in the body of 5
- Converted to 5-hydroberoxyeicosatetraenoic acid (5-HPKTB) by lipoxygenase, which is further metabolized and produced.

By the way, a series of metabolites that are produced when 5-HPFiTK is metabolized and have two consecutive conjugated double bonds are called leukotri
ne, ILTs), and 8RS-A is this L
It has been confirmed that it is a mixture of several types of Te. Furthermore, it has been reported that LTe other than SRS-A includes a substance that allows light to pass through blood vessels.

The inhibitor of 5-lipoxygenase is 5-lipoxygenase from arachidonic acid.
It inhibits the conversion to HPBTE and its metabolite LTs
inhibits the release of Therefore, inhibitors of 5-lipoxygenase are useful as therapeutic agents for various diseases caused by SRS-A and other LT days, such as bronchial asthma caused by allergic diseases, rhinitis, atopic dermatitis, and inflammation.

This 5-lipoxygenase inhibitor has attracted attention as a completely new anti-allergic agent or anti-inflammatory agent, and much research has been conducted, but nothing that can be put to practical use has yet been found.

In view of these circumstances, the present inventor has conducted intensive research on a series of aromatic amide carboxylic acid derivatives having anti-allergic effects, and as a result, by introducing a halogen into the α-position, 5-lipoxygenase inhibitory activity has been achieved. It was discovered that this increases, and based on this finding, the present invention was accomplished.

That is, the present invention provides a novel α-haloaromatic amide carboxylic acid derivative having 5-lipoxygenase inhibitory activity, represented by the general formula (in which Y, R', R2 and X have the same meanings as above) or a pharmaceutically acceptable salt thereof, and an antiallergic agent comprising the α-haloaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof.

The α-halo aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention is a new compound, and can be produced as follows.

For example, by reacting an aromatic amide carboxylic acid derivative represented by the general formula (in which Y and R2 have the same meanings as above) with a chlorogenating agent such as bromine or chlorine, X' is a halogen atom, and x, y and R2 have the same meanings as above). Alternatively, by directly treating with water, alcohols such as methanol or ethanol, or carboxylic acid salts such as sodium acetate at room temperature or under heat to replace the halogen atom at the β position with a hydroxyl group, lower acyloxy group, or lower alkoxyl group. can be manufactured.

The compound represented by the general formula (2) used as a starting material in this production method is a known compound, and the method described in the literature (Japanese Patent Publication No. 50-40710, No. 50
40711, 57-47906).

In order to suitably carry out the above manufacturing method, first, general formula (2)
The compound represented by is dissolved in a suitable solvent, such as chloroform, and an equimolar amount of a halogenating agent, such as a chloroform solution of bromine, is added dropwise to the solution while stirring under cooling. After the dropwise addition, the solution is further stirred for a while under cooling or heating. After the reaction, the reaction mixture is concentrated under reduced pressure, and the resulting residue is recrystallized from a suitable solvent to obtain an α,β-dihaloaromatic amide carboxylic acid derivative represented by general formula (6). This compound is then treated in a suitable solvent or directly with water, alcohols or carboxylic acid salts. For example, the compound is dissolved in dioxane or dimethyl sulfoxide, water or methanol is added thereto, or it is dissolved in acetic acid, sodium acetate is added thereto, and the mixture is stirred at room temperature or with heating for 1 hour to overnight. After the reaction is complete, concentrate under reduced pressure, add water to the resulting residue and collect the precipitated crystals by filtration, or extract the solution with a suitable solvent, wash with water, dry, and then distill the solvent under reduced pressure. The residue is recrystallized from an appropriate solvent to obtain the desired product.

The compound represented by the general formula (1) of the present invention is prepared by adding a halogenating agent such as bromine, chlorine, N-bromosuccinimide ( It can also be produced by reacting NBS), N-chlorosuccinimide (NO8), etc.For example, the compound of general formula (21) is dissolved in a mixture of methanol and chloroform, and a chloroform solution of bromine is added under cooling. By dropping the compound dropwise, stirring in a room source for 1 to several hours after dropping, and treating according to a conventional method, a compound of the corresponding general formula (1) in which R1 is a methoxy group and X is a bromine atom can be obtained. The compound of formula (2) is dissolved in dimethyl sulfoxide, and an appropriate amount of water and NBS are added to the solution.
is added, stirred at room temperature for 1 to several hours, and treated according to a conventional method to form R with the corresponding compound of general formula (1).
A compound in which 1 is a hydroxyl group and X is a bromine atom is obtained.

Carboxylic acids having a hydrogen atom in the compound represented by the general formula (1) of the present invention can also be produced by hydrolyzing the corresponding esters in which R2 is a lower alkyl group according to a conventional method. Further, these carboxylic acids can be converted into pharmaceutically acceptable salts according to conventional methods. Examples of such salts include inorganic salts such as sodium salts, potassium salts, and calcium salts, and salts with organic bases such as ethanolamine, morpholine, and dimethylaminoethanol.

The compound represented by the general formula (1) of the present invention has several structural isomers. For example, there are two stereoisomers of threo and erythro depending on the mutual relationship of the configurations of the substituents R1 and X. The production ratio of such isomers varies depending on the starting materials, production method, reaction conditions, etc., and each isomer can be obtained singly or as a mixture.

Unless otherwise specified, the α-no-ro aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention includes:
Any of these isomers are included.

As the α-no-ro aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention, for example, 2-bromo-N
-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl)-6-hydroxypropionamide, 6
-acetoxy-2-bromo-N-(2-carboxyphenyl)=3-(3,4-dimethoxyphenyl)globionamide, 2-bromo-N-(2-carboxyphenyl)-6-(3,4- dimethoxyphenyl)-3-methoxypropionamide, 2-bromo-N-(2-carboxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-5-methoxypropionamide, 2-bromo-3-(s , 4-dimethoxyphenyl)-3-hydroxy-N-(2-methoxycarbonylphenyl)gropionamide, 6-acetoxy-2-bromo-3-(3,4
-dimethoxyphenyl)-N-(2-meth)-4-cyclocarbonylphenylprobionamide, and the like.

The α-haloaromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof is obtained by converting 5-
It strongly inhibits the conversion to HPKT and suppresses the release of LTs such as 5R8-A, which is a metabolite of 5-HPETE. Therefore, the compound of general formula (1) or a pharmaceutically acceptable salt thereof of the present invention includes 5R8-A and other LTs.
It is useful as a therapeutic agent for diseases caused by allergic diseases, such as bronchial asthma, rhinitis, atopic dermatitis, and inflammation.

The inhibitory activity of the compound represented by the general formula (1) of the present invention or its pharmaceutically acceptable salt against 5-lipoxygenase can be detected by the extremely unstable 5-HPIi; TK of the metabolite of arachidonic acid by 5-lipoxygenase. It is confirmed by using 5-hydroxydoeicosatetraenoic acid (5-HETK), which is produced by the decomposition of 5-HPliiTl by peroxidase, as an indicator, and is usually used at a concentration of 1 to 3M. For example, 3-acetoxy-2-bromo-N-(2-carboxyphenyl)-3-
(3,4-Dimethoxyphenyl)gropionamide exhibits an inhibitory activity of 41°5±7.5% at a concentration of 10″M.

The antiallergic agent of the present invention comprising the α-no-ro aromatic amide carboxylic acid derivative represented by general formula (1) or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, or to mammals including humans. Administration can be by any suitable method of administration, such as intramuscular, subcutaneous or intravenous administration. The drug is administered in various commonly used dosage forms, such as solid preparations such as powders, granules, tablets, and capsules, liquid preparations such as solutions, suspensions, and syrups, and injections.

Such formulations are prepared by techniques commonly practiced in the field of pharmaceutical science. For example, powders can be obtained by adding appropriate excipients, stabilizers, solubilizing agents, etc. to the base drug, mixing the mixture uniformly, and dispensing the mixture in fixed amounts. Granules are made by adding excipients, binders, disintegrants, etc., kneading them, granulating them, drying them,
Obtained by sorting. Tablets are made by adding excipients, binders, disintegrants, etc. and mixing them uniformly, or by making them into granules, adding lubricants, etc., and then compressing the tablets to contain a certain amount of herbal medicine. can get. By further coating these tablets with various coating agents, sugar-coated tablets, film-coated tablets, enteric-coated tablets, etc. can be obtained. Capsules can be obtained by using the herbal medicine as it is or by diluting it to an appropriate concentration to prepare a powder or granules, and then filling a gelatin capsule in a fixed amount. Solutions and suspensions are prepared by dissolving or suspending in purified water a solubilizing agent, a suspending agent, and, if necessary, a stabilizer, a preservative, and the like. Syrups are obtained by dissolving or suspending herbal medicines in sucrose solution or simple syrup. Additives such as sweeteners and coloring agents can also be added to these preparations as necessary.

Liquid preparations for injection are made into solutions, suspensions, or emulsions using solubilizing agents, suspending agents, emulsifiers, etc. in a sterile environment, and if necessary, stabilizers, buffering agents, preservatives, and isotonic agents. It can be obtained by adding such ingredients and filling a certain amount into a container. In the case of a solution, it can also be sterilized by filtration or heat sterilization after preparation. Solid preparations for injection are produced by manufacturing powdered preparations using aseptic procedures and filling fixed amounts into containers, or by dissolving them in a solvent such as purified water and filling fixed amounts into containers, and then freeze-drying. can get.

The content of the antiallergic agent in these preparations needs to be an appropriate amount to achieve the desired antiallergic effect and to avoid any undesirable side effects. In the case of tablets and capsules that are usually administered orally, it is convenient to have 1 to 5 Dm9 per tablet or capsule, and in the case of injection preparations, the content is about 0.1 to 10 Dm9 per ampoule or 1 vial. It is convenient to do so.

When actually administering such a preparation, the dosage varies depending on the type and severity of the patient's disease, as well as the age, sex, and weight of the patient, and therefore needs to be changed depending on the individual condition of the patient. Usually, it is preferably administered in the range of 1 to 1,000 in the case of oral administration per adult per day, and in the range of 0,1 to 100 in the case of parenteral administration.

The present invention will be explained in more detail below using reference examples and examples. Note that all the melting points of the compounds in each Reference Example and Example are uncorrected.

Reference example 1 4) -N-(2-carboxyphenyl)-6-(3,4
-dimethoxyphenyl)propenoic acid amide 32.7.9
was dissolved in a mixture of 40 ml of methanol and 700 tel of chloroform, and while stirring under water cooling, 16.0 ml of bromine was dissolved.
A chloroform solution containing p was added dropwise.

After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. The obtained residual crystals were recrystallized from chloroform-hexane to give erythropolymer with a melting point of 198-201°C.
2,3-dibromo-N-(2-carboxyphenyl)-
3-(S,4-dimethoxyphenyl)propionamide 29.9! I got 1.

Elemental analysis value (as C18HI Y Br, No)
04 N% Nchi calculated value 44.5B 5.52 2.88 Actual value 44
．． 74 3.41 2.75 Infrared absorption spectrum (K
Br) νN)I: 3300α-1 vOo: 1675 cytr' Nuclear magnetic resonance spectrum (90MHz, d,-acetone) δ: 3.89 (3H, 8), 3.91 (3
H, e), 5.66 (2H, θ), 6.9-8.9
(7H, m) Reference Example 2 (Homogenous 5-(3,4-dimethoxyphenyl)-N-(
2-methoxycarbonylphenyl)propenoic acid amide 1
Dissolve 2,7.9 in 20OR/chloroform.

To this solution, while stirring under water cooling, 40@l of a chloroform solution containing 6.0 g of bromine was added dropwise over 30 minutes, and the solution was further stirred for 1 hour after the dropwise addition. The reaction solution was then concentrated under reduced pressure, and hexane was added to the residue for crystallization. The crystals were dissolved in benzene, treated with activated carbon, and recrystallized by adding hexane, with a melting point of 129.5-131°C.
(Colored) Erythro-2,3-dibrome-5-(3,4
11.5 fl of -dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide was obtained.

Elemental analysis value (as C1e Hl 9 Br2No)
0% N% N% Calculated value 45.53! 1,82 2.79 Actual value 4
5.70 3,74 2.67 Infrared absorption spectrum (
KBr) νNH: 5260 rye-” νC!Q: 1710α-1, 169oα-1 Nuclear magnetic resonance spectrum (90MB2, 0DO1!3) δ
: S, 85 (3H, s), 3.67 (3H
, e), 3.90 (5H, s), 4.85 (I
H, d), 5.46 (IH, (1), 6.7~y, s
(5H.

m), 8.05 (IH, da) S8,74 (I
H, cud), 11.53 (IH, 8) Example 1 2.0 g of erythro-2,3-dibrom-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide dimethyl sulfoxide 1
After stirring at room temperature for 16 hours,
80 g of water was added and stirred for 2 hours. Next, the precipitated viscous crystals were collected by filtration and washed with diisopropyl ether to give erythro-2-bromo-
1.7 g of 5-(5,4-dimethoxyphenyl)-3-hydroxy-N-(2-methoxycarbonylphenyl)propionamide was obtained.

Elemental analysis value (as C19H2゜BrNO6) 0% N
% N% Calculated value 52.07 4,6Q 3.20 Actual value 51
,70 4,65 2.96 Infrared absorption spectrum (K
Br) νOH: 3440 scratches-! νCo: 168o as″ Nuclear magnetic resonance spectrum #(90MH2, 0Dcz3) δ-
: 5,76 (5H, B), 3.79 (3a, E
+ input 3.87 (5H, θ), 4.48 (IH,
a), 5.08 (IH, d), 6.6-7.7
(5H.

m), 8.00 (IH, ad), 8.58 (
IH, da), 11.45 (IH, θ) Example 2 Erythro-2,3-dibromo-N-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl)propionamide 487~ was treated with dioxane It was dissolved in a mixture of 50ml and 5oul of anhydrous methanol, and stirred overnight at room temperature. The reaction solution was then concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residual crystals were recrystallized from chloroform-hexane to give a melting point of 179-18.
Erythro-2-bromo-N-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl)-5- at 1°C.
Methoxypropionamide 297 was obtained.

Elemental analysis value (as C+ * H2o BrN0.l)
0% H-ch N-ch calculated value 52.07 4.60 3.20 Actual value 52
,13 4.60 2.96 Infrared absorption spectrum (K
Br) νcQ: 1685 Cm-”, 1660 Cm-
'Nuclear magnetic resonance spectrum (90MH2, (!DOI!,
) δ: 3j1 (3H, Il+), 3.76 (3
H, θ included 5.135 (6■, B), 4-69 (
2H, 8), 6, y-y, 3 (4H, m), 7.4
5-i, 2s (IH, m), 8.10 (IH, ad
), 8.74 (IH, (1) , 8.95 (IH
, tar.

11.41 (IH,S) Example 3 Erythro-2,3-dibromo-N-(2-carboxyphenyl)-3-(5,4-dimethoxyphenyl)propionamide 4.87. ! i', sodium acetate 0.86
Stir a mixture of fl and acetic acid 500g/5.
Heated at 0°C for 2 hours. The reaction solution was then concentrated under reduced pressure, water was added to the residue to crystallize it, and the crystals were collected by filtration, washed with water, and recrystallized from chloroform-hexane to give a crystal with a melting point of 140-142°C (decomposed). Erythro-6-acetoxy-2-bromo-N-(2-carboxyphenyl)-5
-(3,4-dimethoxyphenyl)propionamide 5
．． I got 769.

Elemental analysis value (for 02°.BrN0.) Cchi Hchi Nchi Calculated value 51,51 4j2 3.00 Actual value 5j,
27 4.24 2.86 Infrared absorption spectrum (KB
r) pNH: 3280 cm'' ν00: 1750 tytt-, 1670 pieces-1 nuclear magnetic resonance spectrum pv (90MH2, d, -DMSO
) δ: 2. DO(3H, θ), 168 (3H, e
), 3.71 (3H, θ), 5.12 (1H, d
), 6.05 (H, d), 6.85-8.4 (
7H, m), 11.40 (lH, s) Example 4 Erythro-2,5-dibrom-5-(5,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide 2. Erythro-3-acetoxy-2-from-5-(3,4-
1.7 g of dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)gropionamide was obtained.

Elemental analysis value (as 02, H2□BrN□) 0% N
% Nchi calculated value 52.51 4.62 2.92 Actual value 52
．． 42 4.54 2.76 Infrared absorption spectrum (K
Br) νNH2 3250 C"' ν(!O: 1720 cm', 1690 cm'
Nuclear magnetic resonance spectrum (90MHz, 0DOz3)
δ: 2.05 (3H, e), 171 (3H,
θ included 5.76 (3H, s), 3.84 (3H, s
), 4.61 (IH, d), 6. u (IH, a
), 6.6-7.8 (5H, m), 8.05 (I
H.

dd), 8.66 (IH, dd), ii, s.

(IH, 8) Example 5)-N-(2-carboxyphenyl)-3-(3,4
-dimethoxyphenyl)propenoic acid amide 6.55 l
was dissolved in 250*/ of anhydrous dioxane, and while stirring under water cooling, a solution of 50*/ of anhydrous dioxane containing 1.031/ of bromine was prepared. / was dropped. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, then 500 txt of water was added, and the mixture was further stirred for 1 hour.

The reaction solution was then concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was crystallized by adding methylene chloride to a melting point of 165.
Erythro-2-bromo-N-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl) at ~167°C
-3-Hydroxypropionamide 7.519 was obtained.

Elemental analysis value (as 01, H18BrNO6) Cchi N
% N% Calculated value 50.96 4゜28 3jO actual value 50,
78 4,27 3.12 Infrared absorption spectrum (KB
r) vOH: 3450 or" νno: 1670α-1 Nuclear magnetic resonance spectrum/l/(90, MH2, d, -DM
SO) δ: 3.67 (3H, e), 5.70
(3H, s), 4.61 (IH, d), 4.92
(IH, d), 6.85-8.55 (7H, m)
, 11.47 (IH,8) Example 6)-N-(2-carboxyphenyl)-3-(6,4
-dimethoxyphenyl)propenoic acid amide 3.0,!
9 was dissolved in 15 ml of dimethyl sulfoxide, and N
- After adding 1.3 g of bromoconophosphate imide and 2 ml of water, the mixture was stirred at room temperature for 3 hours. Next, water was added to the reaction solution, which was then extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was crystallized by adding methylene chloride to a melting point of 165.
Erythro-2-bromo-N-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl) at ~167°C
-3-Hydroxypropionamide 38! I got j. Have you conducted an infrared absorption spectrum and nuclear magnetic resonance spectrum on this product? It was identical to that of the compound obtained in 1I5.

Example 7 ((1)-N-(2-carboxyphenyl)-6-(4
-Hydroxy-6-medoxyphenyl)propenoic acid amide (1.50 J) in methanol (5 ml) and chloroform (100 J)
A chloroform solution containing 0.80 lI of bromine was added dropwise while stirring under water cooling. After the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residual crystals were recrystallized from chloroform-hexane to give erythropolymer with a melting point of 150-153°C (decomposition).
2-bromo-N-(2-carboxyphenyl)-5-<
1.61 g of rhomethoxypropionamide (4-hydromethoxyphenyl) was obtained.

Elemental analysis value (as 01g Hl @ BrNO6) 0
% H-chi N-chi Calculated value 50.96 4.28 3.30 Actual value 50
．． 54 4.51-I21 infrared absorption spectrum (KB
r) νOH: 34oOtyn" νNH: 3225 cyt-" ν00: 1665α-1 Nuclear magnetic resonance spectrum (90MH2, eL6-DMSQ
) δ: 3,12 (3H,s), 3.69 (
31(.

S), 4.4B, 4.65 (2H, AB-q)
, 6.7-8.5 (7H, m), 11.40 (
IH, s) Example 8 5-Lipoxygenase inhibitory activity Separation and preparation of 5-lipoxygenase RBIJ-1 (Dainippon Pharmaceutical Co., Ltd.)
After culturing at 37° C. and 5% CO 2 using E medium, cells were collected by centrifugation. The cells were soaked in phosphate buffer (50mM potassium hydrogen phosphate, 1mM FiD).
2 in 10%-ethylene glycol, pH 7,4) to T.
．． The cells were suspended at 0x10 cells/II/cells and disrupted by ultrasound. After sonication, centrifugation was performed at 4° C. for 100,000,000 minutes using an ultra-high-speed refrigerated centrifuge, and the supernatant was used as a 5-lipoxygenase enzyme solution.

Production of 5-HKTE by 5-lipoxygenase and inhibitory activity by drugs 50 mM potassium phosphate buffer (pi47.4)
Inside, CaC! I! 2. GSH and ATP were added to final concentrations of 1 mM, 1 mM, and 2 mM, respectively, to prepare a reaction solution. A 5-lipoxygenase enzyme solution was added thereto, and after incubation at 30°C for 5 minutes, 0.1 μOi of (114Q) arachidonic acid ethanol solution was added and reacted at 30°C for 5 minutes. After the reaction, 5tttl of an ice-cooled mixture of diethyl ether:methanol:0.2M-citric acid (30:4:1) was added, and arachidonic acid and the produced 5
-HliiTE was extracted. The centrifuged upper layer was subjected to thin layer chromatography (developing solvent: petroleum ether: diethyl ether: acetic acid = 15:85:0.1) to separate arachidonic acid and 5-HKTK. After confirming the development positions of both nine compounds by autoradiography, each portion was scraped off and radioactivity was measured using a liquid scintillation counter. 5- HKTE production rate (%)
was determined by the following formula.

The 5-lipoxygenase inhibitory activity of each drug was determined by adding each drug to the reaction solution at a final concentration of 10'-3,10-'M, and increasing the 5-HETE production rate in the control by 1.
00, the reaction inhibition rate (%) of each drug was calculated.

The test results are shown in the table below.

As is clear from the above test results, one compound of the present invention is
It has strong inhibitory activity against 5-lipoxygenase.

Claims (1)

[Claims] 1 General Formula] (Y in the formula may be the same or different, and each is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R1 is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R2 is hydrogen Atom or lower alkyl group, X
is a halogen atom) or a pharmaceutically acceptable salt thereof. 2 general formula (Y in the formula may be the same or different, each is a hydroxyl group, a lower acyloxy group or a lower alkoxyl group, R1 is a hydroxyl group, a lower acyloxy group or a lower alkoxyl group, and X is a halogen atom) The α-halo aromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1. 3 general formula (Y in the formula may be the same or different, each being a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R1 is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R2' is a lower alkyl group; or a halogen atom) The α-...ro aromatic amide carboxylic acid derivative according to claim 1, which is represented by: The α-...ro aromatic amide carboxylic acid derivative according to claim 2, represented by the formula 4, or a pharmaceutically acceptable salt thereof. 5. The α-halo aromatic amide carboxylic acid derivative according to claim 2 or a pharmaceutically acceptable salt thereof, represented by Formula 5. 6. The α-halo aromatic amide carboxylic acid derivative according to claim 2, represented by Formula 6, or a pharmaceutically acceptable salt thereof. 7. The α-haloaromatic amide carboxylic acid derivative according to claim 2, represented by Formula 7, or a pharmaceutically acceptable salt thereof. The α-halo aromatic amide carboxylic acid derivative according to claim 3, which is represented by formula 8. The α-haloaromatic amide carboxylic acid derivative according to claim 3, which is represented by formula 9. 10 General formula (Y in the formula may be the same or different, each being a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R1 is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group; R2 is a hydrogen atom or a lower alkyl group; An anti-allergic agent comprising an α-haloaromatic amide carboxylic acid derivative represented by (X is a halogen atom) or a pharmaceutically acceptable salt thereof. 11 General formula (Y in the formula may be the same or different. Each is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group, R1 is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group, and X is a ) rogen atom) The anti-allergic agent according to claim 10, which comprises the α-haloaromatic amide carboxylic acid derivative shown above or a pharmaceutically acceptable salt thereof. 12 general formula (Y in the formula may be the same or different, each is a hydroxyl group, a lower acyloxy group or a lower alkoxyl group, R1 is a hydroxyl group, a lower acyloxy group or a lower alkoxyl group, R2' is a lower alkyl group. 11. The antiallergic agent according to claim 10, which comprises an α-halo aromatic amide carboxylic acid derivative represented by: