JPS60146857A - 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> and R<2> are halogen, H, or R<1> and R<2> are bonded to each other to form chemical bond; R<3> is H, lower alkyl; X is halogen). EXAMPLE:2,3-Dibromo-N-(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl)propion amide. USE:An antiallergic. Showing improved inhibitory activity against 5-lipoxygenase. PREPARATION:An alpha,beta-dihalocarboxylic acid shown by the formula II (R' is halogen) or its reactive derivative is reacted with anthranilic acid shown by the formula III or its ester in a solvent such as methylene chloride, etc. in the presence of a base such as pyridine, etc. at room temperature - under heating, to give a compound shown by the formula I (when R<1> is halogen and R<2> is H).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel α-haloaromatic amide carboxylic acid derivative and an antiallergic agent comprising this compound. may be the same or different from each other, and each is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group, and R1 and R2 are respectively a rogen atom and a hydrogen atom, or combine with each other to form a chemical bond. , R3 is a hydrogen atom or a lower alkyl group, and X is a halogen atom), or a pharmaceutically acceptable salt thereof;
and (c) an anti-allergic agent comprising the above-mentioned α-haloaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof.

In recent years, in the fields of allergy and inflammation, the chemical mediator Tough (
C! chemical mediator), BRB-A (Slow reacting 5
ubstance ofanaphylaxis) has been attracting attention. On this day, R8-A was released from the lungs of sensitized guinea pigs and asthma patients, and is a substance that strongly contracts the smooth muscles of the bronchi and intestinal tract, and is important in atopic asthma and immediate allergic reactions. considered to play a role.

In the 5R8-A, arachidonic acid is 5-
It is converted by lipoxygenase to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is further metabolized and produced. By the way, 5-HPE
Leukotrienes (1eu
kotriene, LTs), and it has been confirmed that R8-A is a mixture of several types of these LTs.

Furthermore, it has been reported that LTs other than EIR8-A include substances that cause redundancy in vascular permeability.

The inhibitor of 5-lipoxygenase is 5-lipoxygenase from arachidonic acid.
inhibits the conversion to HPKTE and its metabolite LT
Inhibits the release of s. Therefore, inhibitors of 57 riboxygenase are useful as therapeutic agents for various diseases caused by 5R8-A and other LTs, 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 inventors have conducted extensive research on a series of aromatic amide carboxylic acid derivatives that have antiallergic effects, and have found that 5-lipoxygenase can be inhibited by introducing a halogen into the α-position. It was discovered that the activity was increased, and based on this finding, the present invention was accomplished.

That is, the present invention provides a novel α-haloaromatic amide having a 5-lipoxygenase inhibitory activity represented by the general formula % (Y, R1, R2, R3 and X have the same meanings as above). The present invention provides an antiallergic agent comprising a carboxylic acid derivative or a pharmaceutically acceptable salt thereof, and the above-mentioned α-...roaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof.

The α-no-ro aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention is a novel compound, and can be produced as follows.

For example, in the compound of the general formula (1), R1 is...a rogen atom and R2 is a hydrogen atom,
' is a halogen atom, and X, Y and R3 have the same meanings as above). fi can be produced by reacting a dihalocarboxylic acid or a reactive functional derivative thereof with anthranilic acid or an ester thereof represented by the general formula C (in which R5 has the same meaning as above).

The α,β-dihalocarboxylic acid represented by the general formula (2) used as a starting material in this production method is:
For example, it can be obtained by adding a halogenating agent such as chlorine or bromine to a nuclear-substituted cinnamic acid represented by (Y in formula C has the same meaning as above).

Examples of the reactive functional derivatives of α,β-dihalocarboxylic acids include acid halides, acid anhydrides, mixed acid anhydrides, and esters, all of which can be produced according to conventional methods. For example, acid halides are
It can be produced by reacting the above α,β-dihalocarboxylic acid with an acid halogenating agent such as thionyl chloride without a solvent or in a suitable solvent.

In the method for producing the α-halo aromatic amide carboxylic acid derivative represented by the general formula (1'), the compound represented by the general formula (3) used as the other raw material is a known compound and is commercially available. It is available as a commercial product, and can also be easily produced by methods described in literature.

In order to suitably carry out this manufacturing method, first, the general formula (
The compound represented by 4) is dissolved in a suitable solvent, such as chloroform, and an equimolar amount of a halogenating agent, such as bromine, in chloroform is added dropwise while stirring under cooling.
After dropping, stir for a while while cooling or heating. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue is recrystallized from an appropriate solvent to obtain α represented by the general formula (2).
, β-dihalocarboxylic acid is obtained. Next, this α,β-dihalocarboxylic acid is reacted with an acid halogenating agent such as thionyl chloride to prepare an acid chloride, and after dissolving this in a suitable solvent such as methylene chloride, an equimolar amount of the general formula (3) is prepared.
The compound represented by and the necessary amount\excess amount of base,
For example, it is added dropwise to a methylene chloride solution containing pyridine.

After the dropwise addition, the reaction mixture is allowed to react at room temperature or under heating for several hours to over ten hours, and the desired product is obtained by treatment and purification according to conventional methods.

Further, the compound represented by the general formula (1') of the present invention is, for example, an aromatic amide carboxylic acid derivative represented by the general formula (Y and R3 in the formula have the same meanings as above) and a halogen such as chlorine or bromine. It can also be produced by adding a curing agent.

The aromatic amidocarboxylic acid derivative represented by the general formula (5) used as a raw material in this production method is a known compound, and the method described in the literature (Japanese Patent Publication No. 50-40
Publication No. 710, Publication No. 50-40711, Publication No. 57-4
7906) can be manufactured according to the method.

In order to suitably carry out the above manufacturing method, first, general formula (5)
The compound represented by is dissolved in a suitable solvent, such as chloroform, and an equimolar amount of a halogenating agent, such as a solution of bromine in chloroporm, is added dropwise to the solution while stirring under cooling. After dropping, stir for a while at room temperature or under heating. After the reaction is complete,
The reaction solution is concentrated under reduced pressure, and the resulting residue is recrystallized from an appropriate solvent to obtain the desired product.

A compound represented by the general formula (1) of the present invention, in which R1 and R2 combine with each other to form a chemical bond, and is represented by the general formula (X, Y and R3 in the formula have the same meanings as above) The compound is represented by the general formula (1')
, can be produced by treating a β-dihaloaromatic amide carboxylic acid derivative with a basic substance to dehydrohalogenate it. Various strong basic substances are used in the dehydrohalogenation reaction in this production method, but 1,5
-diazabicyclo[4,3,0]non-5-ene (DB
N), 1,4-diazabicycloC2,2,2,]octane (DABC!O), 1.8=diazabicyclo[5
,4,0)-7-undecene (DBU) and the like are preferred, and among these, DBU is also preferred.

In order to suitably carry out the above manufacturing method, first, the general formula (1'
) in a suitable solvent such as benzene,
Dissolve in toluene, add 1 to 2 equivalents of DBU, and stir at room temperature or with heating for several hours to over ten hours.

After the reaction is completed, the desired product is obtained by treatment and purification according to conventional methods.

The compound represented by the general formula (1) of the present invention has the following structure:
Several isomers exist. For example, the compound represented by the general formula (1') in which R1 is a halogen atom and R2 is a hydrogen atom includes two stereoisomers of threo and erythro due to the mutual relationship of the configurations of the substituents R1 and X. The compound represented by the general formula (4') in which R1 and R2 combine with each other to form a chemical bond has two types of geometric isomers: 8-isomer and 2-isomer depending on the arrangement of the nuclear substituted phenyl group and X. There is.

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.

The α-halo aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention includes any of these isomers, unless otherwise specified.

The carboxylic acids in which R3 is a hydrogen atom in the compound represented by the general formula (1) of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method. 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 dimethylamineethanol.

Examples of the α-no-ro aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention include 2,3-dibromo-N-(2-carboxyphenyl)-3-(3,4-
dimethoxyphenyl)propionamide, N-(2-carboxyphenyl)-2,3-Schiff C1/l/-3
,-(3,4-cy)toxyphenyl)flopionamide, 2,3-dibromo-N-(2-carboxyphenyl)-3-(3,4-diacetoxyphenyl)fropionamide, 2,3- Dibromo-3-(3,4-dimethoxyphenyl)-N-(2-,methoxycarbonylphenyl)fropionamide, 2-bromo-3-chloro-3-(
3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)flopionamide, 3-(4-acetoxy-3-methoxyphenyl)-2,3-dibromo-
N-(2-methoxycarbonylphenyl)flopionamide, 2,3-dibromo-3-(3,4-diacetoxyphenyl)-N-(2-methoxycarbonylphenyl)
Flopionamide, 2-bromo-N゛, -(2-carboxyphenyl)-3-(3,4-dimethoxyphenyl)
Propenoic acid amide, 2-bromo-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide, 2-bromo-3-(3,4-diacetoxyphenyl)-N- (2-methoxycarbonylphenyl)propenoic acid amide, 3-(4-acetoxy-
Examples include 3-methoxyphenyl)-2-bromo-N-(2-methoxycarbonylphenyl)propenoic acid amide. Among these, particularly preferred compounds are erythro-2,3-dibromo-N-(2-carboxyphenyl-3-(3,4-diacetoxyphenyl)propionamide, ■)-2-bromo-N-(2 -carboxyphenyl)-3-(3,4-dimethoxyphenyl)propenoic acid amide, and the like.

The α-no-ro aromatic amide carboxylic acid derivative represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof can be obtained from arachidonic acid by 5-lipoxygenase.
- Strongly inhibits the conversion to HPFiTK,
It suppresses the release of LTs such as 5R3-A, which is a metabolite of TFi. Therefore, the compound of general formula (1) of the present invention or a medically acceptable salt thereof can be used to treat diseases caused by LTs including 5R8-A, such as bronchial asthma caused by allergic diseases, rhinitis, atopic dermatitis, or inflammation. It is useful as a therapeutic agent.

The inhibitory activity of the compound represented by the general formula (1) of the present invention or its pharmaceutically acceptable salt against 5-lipoxygenase is that 5-HPFiTE, a metabolite of arachidonic acid by 5-lipoxygenase, is extremely unstable and cannot be detected. Since it is difficult to identify, it is confirmed by using 5-hydroxyeicosatetraenoic acid (5-HFiTFi), which is produced by decomposing 5-HPETK with peroxidase, as an indicator.

The inhibitory effect of the above compounds on 5-lipoxygenase is seen in a dose-dependent manner at a concentration of approximately 10-6 to 10-8M; for example, erythro-2,3-sifurome-N
-(2-carboxyphenyl)-3-(3,4-diacetoxyphenyl)propion 10-' M
It showed an inhibitory activity of 99.0 and 2% at a concentration of 9.2
It exhibits a 50% inhibitory effect at a concentration of 10-'M.

The antiallergic agent of the present invention comprising the α-haloaromatic amide carboxylic acid derivative represented by general formula (1) or a pharmaceutically acceptable salt thereof is effective for mammals including humans.
Administration can be by any suitable method of administration, such as oral, parenteral, intramuscular, subcutaneous or intravenous administration. For administration, various dosage forms commonly used, such as solid preparations such as powders, granules, tablets, and capsules, solutions, suspensions,
It is administered as a liquid preparation such as syrup or as an injection.

Such preparations are prepared by Method J, which is 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 granules, adding lubricants, etc., and then compressing the tablets to contain a certain amount of the active ingredient. can get. By further coating these tablets with various coating agents, sugar-coated tablets, film-coated ink tablets, enteric-coated tablets, etc. can be made. Capsules can be obtained by preparing the main drug as is or by diluting it to an appropriate concentration to prepare a powder or granules, and then filling a fixed amount of the drug into capsules made of gelatin or the like. Solutions and suspensions are
It is prepared by dissolving or suspending it in purified water with the addition of solubilizing agents, suspending agents, and if necessary stabilizers and preservatives. Syrups can be obtained by dissolving or suspending the active ingredient in a 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. For solid preparations for injection, either manufacture powdered preparations using aseptic operations and fill fixed amounts into containers, or dissolve them in a solvent such as purified water and fill fixed amounts into containers.A.

It is then obtained by freeze-drying.

The content of the antiallergic agent in these preparations must 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 contain about J to 50 m9 per tablet or capsule, and in the case of injection preparations, the content should be about 90.1 to 10 m9 per ampoule or one vial. is convenient.

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. It is usually preferable to administer the drug per adult per day in the range of 1 to i,ooo■ in the case of oral administration, and in the range of 0.1 to ioo■ 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 (K) - To a solution of 10.4F of -3-(3,4-dimethoxyphenyl)propenoic acid dissolved in 500% of dry chloroform, 8.8% of bromine was added. Dry chloroform solution containing Of20
- was added dropwise over 30 minutes while stirring under water cooling, and the mixture was further stirred for 1 hour after the addition. Next, the reaction solution was concentrated under reduced pressure, and the obtained white crystals were recrystallized from chloroform-hexane to give erythro-2, having a melting point of 144-147°C.
15.22 of 3-dibromo-3-(3,4-dimethoxyphenyl)propionic acid was obtained.

Elemental analysis value (as C11H12Br2o4) Section C H
Coefficient calculation value 35.90 3.29 Actual value 35.92 3.06 ・Groove outer line absorption spectrum (KBr) ν'OH: 3300crn-” νCO°1750.x” Nuclear magnetic resonance spectrum (90MHz, d6DMSO)
δ: 3.70 (6H, s), 5.28 (IH, d).

5.48 (IH, d), 6.8-7.4 (3H, m
).

9.4-10.0 (IH,br) Example 1 Tsukuda)-'-N-(2-carboxyphenyl)-3-(3
,4-dimethoxyphenyl)propenoic acid amide 32.7
Dissolve 40% of methanol and 700% of chloroform and stir while cooling with water to dissolve 36% of bromine. A chloroform solution containing Of 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 erythro-2 having a melting point of 198-201°C.
,3-dibromo-N-(2-carboxyphenyl)-a
-(3,4-dimethoxyphenyl)propionamide 2
9.9 f was obtained.

Elemental analysis value (as C1'BH17Br2NO5) 0%
H poly N% Calculated value 44.38 3,52 2.88 Actual value 44
．． 74 3.41 2.75 Infrared absorption spectrum (K
Br) 1 νNH: 3300t:rn ν(!O:1675 nuclear magnetic resonance spectrum (9QMHz, d6-acetone)
δ: 3.89 (3H,s), 3.91 (3
H, θ).

5.66 (2H,s), 6.9~8.9 (7
H,m) Example 2 (E)-N-(2-carboxyphenyl)-3-(3,
4-dimethoxyphenyl)propenoic acid amide 6.54t
was dissolved in a mixture of 20 - acetic acid and 40 - dry chloroform, and 2.94 f of N-chlorosuccinimide and 0.4 f of N-chlorosuccinimide were dissolved.
60m7 of chloroform solution containing N hydrogen chloride! was added and stirred at room temperature for 16 hours.

Next, the reaction solution was concentrated under reduced pressure, and then xylene was added to the residue, and the mixture was concentrated under reduced pressure. Next, water was added to the residue, extracted with chloroform, 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-hexadiene to give a melting point of 212.
N-(2-carboxyphenyl)-2,3 at ~216°C
-Cyclo-3-(3,4-dimethoxyphenyl)propionamide 6.60 f was obtained. This is a mixture of threo and erythro bodies in a ratio of about 1:1.

Elemental analysis value ((as !1Bn17C12NO5) C section H section N% Calculated value 54.28 4.30 3.52 Actual value 53
．． 92 4.31 3.39 Infrared absorption spectrum (K
Br) νNH: 3160cIn-' νCo: 1690. -rn-1+ 1660crn
-'Nuclear magnetic resonance spectrum (90MHz, d6-acetone) δ: 3.73 (s), 3.78 (s),
5.10.5.65 (AB-q), 5.18.5.4
2 (AB-q), 6.8-8.8 (m), 11.
62 (s), 11.82 (s) Example 3 ■1-N-(2-carboxyphenyl)-3-(3,4
-diacetoxyphenyl)propenoic acid amide L91 f
was dissolved in a mixture of 10+d of acetic acid and 200-d of chloroform, and while stirring under water cooling, a chloroform solution containing 0.8t of bromine was added dropwise over 6 hours. 2 more after dripping
After stirring for an hour, the reaction solution was concentrated under reduced pressure, 100-diethyl ether was added to the residue, and insoluble matter was filtered off.
The filtrate was concentrated under reduced pressure. The obtained residual crystals were recrystallized from benzene-hexane to obtain erythro-2,3-dibromo-N-(2-carboxyphenyl)-a-(3,4-diacetoxyphenyl) having a melting point of 151-152°C. 2.05 t of fropionamide was obtained.

Elemental analysis value (as C2oH17Br2NO7) 0%
8% N coefficient calculated value 44.22 3.15 2.58 Actual value 44
．． 33 3,10 2.41 Infrared absorption spectrum (K
Br) νNH: 3280ctn-' νCo: 1760L:rn, 1690cfn,
1670. :rn-' nuclear magnetic resonance spectrum (90MH
z, d6-acetone) δ: 2.29 (6H, s),
5.43 (IH, d).

5.62 (IH, d), 7.1-8.8 (7H
, m).

11.60 (IH,s) Example 4 (E) -3-(3,4-dimethoxyphenyl)-N-
(2-,7')oxycarbonylphenyl)propenoic acid amide 12.7f was dissolved in chloroform 200-, and while stirring under water cooling, bromine 6.7f was dissolved. A chloroform solution containing Of was added dropwise over 30 minutes, and the mixture was further stirred for 1 hour. 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 then recrystallized by adding hexane.
2,3-dibromo-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide 11.5F was obtained.

Elemental analysis value (as C+ 9H19Br2NO5) C ratio H ratio N% Calculated value 45.53 3.82 2.79 Actual value 45
．． 70 3.74 2.67 Infrared absorption spectrum (K
Br) νNH: 3260cIn-' νCO: 1710cn4-', 1690crn'-
'Nuclear magnetic resonance spectrum (90MHz, CDCl3
) δ 3.83 (3H, s), 3.87 (3H, s).

3.90 (3H, s), 4.85 (IH, d).

5.46 (IH, d), 6.7-7.8 (5H,
m).

8.05 (IH, da), 8.74 (IH, da).

11.53 (IH, Japan) Example 5 @)-3-(4-acetoxy-3-methoxyphenyl)
Using -N-(2-methoxycarbonylphenyl)propenoic acid amide, erythro-3-(4-acetoxy-3-methoxyphenyl ) -2,3-dibromo-N-(2-methoxycarbonylphenyl)fropionamide was obtained.

Elemental analysis value (as 020H19Br2NO6) 0%
8% N% Calculated value 45.39 3.62 2.65 Actual value 45
．． 68 3.52 2.44 Infrared absorption spectrum (x
Br) νNH: 3225. , crn-' νCO°1760α , 1700z , 1680 side-1
Nuclear magnetic resonance spectrum (90MH2,0DC15) δ:
2.24 (3H, θ), 3.84 (3H, 8).

3.93 (3H, s), 4.82 (IH, d).

5.48 (IH, d), 7.0-8.8 (7H, m).

11.68 (IH, θ) Example 6 ■) -3-(3,4-diacetoxyphenyl)-N-(
2-) l-xycarbonylphenyl)propenoic acid amide by the same procedure as described in Example 4,
Erythro-2,3-dibrome with a melting point of 161-163°C
3-(3,4-diacetoxyphenyl) -N-(2-
methoxycarbonylphenyl)propionamide was obtained.

Elemental analysis value (as C2oH17Br2NO7) 0%
8% N width calculated value 45.27 3.44 2.51 Actual value 45
．． 70 3.55 2.27 Infrared absorption spectrum (K
'Br) νNH: 3250z-" νCo: 1760crn, 1690.:rn-'
Nuclear magnetic resonance spectrum (90MHz, CDC45) δ
: 2.33 (6H, s), 3.94 (3H, s).

4.76 (IH, d), 5.44 (IH, d).

7.0-8.85 (7H, m), 11.58 (IH, s
) Example 7 Erythro 2,3-dibrom-3-(3,4-dimethoxyphenyl)propionic acid 12.01i' was suspended in thionyl chloride 20-'fi, N-dimethylformamide 0.1rn! , and stirred at 50°C for 2 hours.

The reaction solution was then concentrated under reduced pressure to obtain a residual oil. Dry this residual oil with 40m7 of methylene chloride! Dissolve in
This solution was mixed with 4.92 ml of methyl anthranilate and 3 ml of pyridine.
．． 22 dissolved in 40 cm of dry methylene chloride,
The mixture was added dropwise over 30 minutes while stirring under water cooling. After the addition, the mixture was stirred at room temperature for 16 hours, and the reaction solution was washed successively with a 5-hydrochloric acid aqueous solution, a sodium bicarbonate aqueous solution, and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The resulting residue was crystallized by adding hexane, and recrystallized from benzene-hexane to give erythro-2-bromo-3-chloro-3-(3,4-dimethoxyphenyl)- having a melting point of 130-132°C. N-(2-methoxycarbonylphenyl)propionamide io', sr was obtained.

As elemental analysis value CC19H19BrCtN05) 0%
8% N% Calculated value 49.96 4.19 3.07 Actual value 49
．． 99 3.97 2.94 Infrared absorption spectrum (K
Br) νNH', 32606n' νCO° 1710crn-', 1690z' Nuclear magnetic resonance spectrum (90MHz, CDC73) δ 3.
82 (3H, s), 3.85 (3H, e).

3.90 (3H, s), 4.67 (IH, d).

5.39 (LH,d), 6.7~7.7 (5
H, m).

8.05 (IH, da), 8.74 (LH, da).

11.50 (IH,s) Example 8 Erythro-2,3-dibromo -3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide 7.51 was suspended at room temperature for 17.
Stirred for 5 hours. Next, insoluble matter was removed through a filtration side, and the filtrate was washed successively with a 5-hydrochloric acid aqueous solution, a sodium bicarbonate aqueous solution, and water, and then dried over anhydrous magnesium nitrate, and the solvent was distilled off under reduced pressure. Hexane was added to the resulting residual crystals, the crystals were collected by filtration, and the crystals were recrystallized from benzene-hexane to give 2-bromo-3-(3,4-)-2-bromo-3-(3,4-
3.42 of dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide was obtained.

Elemental analysis value (as 019HIBBrNO5) 0% 8
% N% Calculated value 54.30 4.32 3.33 Actual value 54
．． 23 4.23 3.09 Infrared absorption spectrum (K
Br) νNH: 3200on-' νCo: 1700crn', 1650crn-' Nuclear magnetic resonance spectrum (90MH2, CDCl3) δ
3.87 (6H, s), 3.89 (3H, θ)
.

6.8-7.7 (5H, m)', 8.05 (IH, (1
(1).

8.30 (IH, s), 8.78 (IH, 4d).

11.95 (IH,s) The mother liquor was concentrated under reduced pressure and the residue was recrystallized from benzene-hexane to give @)-2-bromo-a-(3,4-dimethoxyphenyl) with a melting point of 110-111°C. )-N-(2-
Methoxycarbonylphenyl)propenoic acid amide 2. ]
I got 1.

Elemental analysis value (as C19HIBBrNO5) 0% H
N% Calculated value 54.30. 4.32. 3.33 Actual measurement value
54.39 4. ．． 72 3.36 Infrared absorption spectrum (KBr) νNH: 3200 cm-'C061690L:rn" + 1660crn-'
Nuclear magnetic resonance spectrum (90MH2, CDC1y, )
δ: 3.62 (3H, s), 3.75 (3H, 6).

3.78 (3H, s), 6.7-7.8 (6H, m).

8.02 (LH, da), 8.79 (IH, dd).

11.32 (IH,s) Example 9 (E)-2-Pro, rom-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide 0.3Of was added to ethanol 15ml To the suspension was added IN aqueous sodium hydroxide solution 7 [0,82-], and the mixture was stirred at room temperature for 7 hours. The reaction solution was then concentrated, and the residue was washed with diethyl ether and methylene chloride.
A 10% aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residual crystals were recrystallized from diethyl ether-hexane to give a melting point of 161.5~
] 0.17f of -2-bromo-N-(2-carboxyphenyl)-3-(3,4-sil)xyphenyl)propenoic acid amide was obtained at 63°C.

゛・Elemental analysis value (as C18H16BrNO5) 0%
H factor N% Calculated value 53.22 3.97 3.45 Actual value 53
．． 10 3.90 3.23 Infrared absorption spectrum (K
Br) νNH: 32506 seats-1 νCo: 1670cm-' Nuclear magnetic resonance spectrum (90MHz, d6-DMSO
) δ: 3.49 (3H, e), 3.67 (3H, s)
.

6.7-7.8 (6H, m), 7.96 (IH
, ad).

8.50 (lH, dd), 11.55 (IH, e) Example 10 Erythro-2,3-dibromo-3-(3,4-diacetoxyphenyl)-N-(2-methoxycarbonylphenyl)propion Amide 7, Ov, was dissolved in 75ml of dry dimethyl sulfoxide and 1,8-diazabicyclo5.
60℃ after adding 4.01-7-undecene2.39
The mixture was allowed to react for 15 minutes. The reaction solution was then poured into water, made acidic with dilute hydrochloric acid, and extracted with benzene. The benzene layer was washed successively with water, an aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

This residue was subjected to silica gel column chromatography (eluent: benzene), and the resulting crystals were purified using benzene.
(El
-2-bromo-3-(3,4-diacetoxyphenyl)
-N-(2-methoxycarbonylphenyl)propenoic acid amide 0.76r was obtained.

Elemental analysis value (as 021HIBBrNO7) Section C H
Relationship N% Calculated value 52.95 3.81 2.94 Actual value 53
．． 37 3.74 2.81 Infrared absorption spectrum (K
Br) νNH: 3170L:rn- νCO: 1770Lm-', 1745crn, 16
90c+++.

1660 trn-' nuclear magnetic resonance spectrum (90MHz, CDCl3)
δ′ 2.11 (3H, s), 2.13 (3H, s).

3.76 (3H, El), 7.18 (IH, El).

6.95-8.75 (7H, m), 11.39
(IH, 8) Example] l Using erythro-3-(4-acetoxy-3-methoxyphenyl)-2,3-dibromo-N-(2-methoxycarbonylphenyl)propionamide, the procedure described in Example 10 was carried out. Melting point 122-124℃ by the same operation as the method.
(El-3-(4-acetoxy-3-methoxyphenyl)-2-bromo-N-(2-methoxycarbonylphenyl)furonic acid amide was obtained.

Elemental analysis value (C2 (as IHIBBrNO6) C section
N% N% Calculated value 53.58 4.05 3.12 Actual value 53
．． 97 4.14 2.94 Infrared absorption spectrum (K
Br) νNH: 3230crn-' νCo: 1770crn-", 1750Lm-',
1685m-'.

1670α-1 nuclear magnetic resonance spectrum (90MHz, CDCl3)
δ: 2.17(3H,s), 3.56(3H,s
).

3.75 (3H, s), 6.9-8.7 (8H, m).

11.44 (IH,s) Example 12 5-lipoxygenase inhibitory activity Separation and preparation of 5-lipoxygenase After culturing RBL-i (Dainippon Pharmaceutical) in MEM-Eargle medium at 37°C under 5% CO2, Multicellular cells were collected by centrifugation. The cells were soaked in phosphate buffer (50%
mM-potassium hydrogen phosphate, ImM-EDTA.

10 cycles - 2, O in ethylene glycol, pH 7,4)
The cells were suspended at a density of 107 cells/rnl, and the cells were destroyed by ultrasonic waves. After the ultrasonication, the mixture was centrifuged at 100,000×G for 60 minutes at 4° C. 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 OaOt2, GSH, and ATP were each added at a final concentration of 1 mM in 50ynM potassium phosphate buffer (pH 7,4).

Add JmM to 2mM and prepare the reaction solution.

Add 5-lipoxygenase enzyme solution to this and heat at 3°C for 50 minutes.
After incubating for a minute, 0.1 μC1 of [1”+40) arachidonic acid dissolved in ethanol was added and reacted at 30° C. for 5 minutes. After the reaction, diethyl ether was cooled on ice.

Methanol: 0.3m7 of 0.2M-citric acid (30:4:1) mixture! was added, arachidonic acid and the generated 5-
HKTFi was extracted. Thin layer chromatography (developing solvent: petroleum ether × diethyl ether) removes the upper layer by centrifugation.
arachidonic acid and 5
-HFiT'Fi was isolated. After confirming the development positions of both compounds by autoradiography, each portion was scraped off after 1°, and the radioactivity was measured using a liquid scintillation counter.

The production rate (%) of 5-HFiTE is calculated by the following formula A+B. In addition, the 5-HIETE production rate in the control was increased by 10
The reaction inhibition rate (correspondence) of each drug was calculated.

The test results are shown in the table below.

Compound No. 2 drug is additionally 10"" + 10'
Calculate the inhibition rate at M and use the regression line υIC! 5Q
(50 inhibitory concentrations) was calculated. As a result, the i(!5° value was 9.2 x 10-6 M.

As is clear from the above test results, the compounds obtained according to the present invention have strong 5-lipoxygenase inhibitory activity.

Patent applicant: Kissei Pharmaceutical Co., Ltd. Agent Akira Agata

Claims (1)

[Claims] l 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, and 6D, R1 and R2 are each one of them) is a halogen atom and a hydrogen atom, or those that combine with each other to form a chemical bond, R3 is a hydrogen atom or a lower alkyl group, and Amidocarboxylic acid derivatives or pharmaceutically acceptable salts thereof. 2 general formula (in the formula, Y may be the same or different, each is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group, R' is a)-rogen atom, R3 is a hydrogen atom or a lower alkyl group, and X is a The α-haloaromatic amidecarboxylic acid derivative according to claim 1, or a pharmaceutically acceptable salt thereof, represented by the formula (a halogen atom). 3 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, R3 is a hydrogen atom or a lower alkyl group, and X is a halogen atom) The α-haloaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to item 1. The α-halo aromatic amide carboxylic acid derivative according to claim 2, represented by 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. The α-halo aromatic amidocarboxylic acid derivative according to claim 2, represented by Formula 6, or a pharmaceutically acceptable salt thereof. The α-haloaromatic amide carboxylic acid derivative according to claim 2, which is represented by Formula 7. The α-haloaromatic amide carboxylic acid derivative according to claim 2, which is represented by formula 8. The α-゛-halo aromatic amide carboxylic acid derivative represented by Formula 9 as claimed in Claim 2. 10. The α-halo aromatic amide carboxylic acid derivative according to claim 2, which is represented by formula 10. 11. The α-halo aromatic amide carboxylic acid derivative according to claim 3, represented by Formula 11, or a pharmaceutically acceptable salt thereof. The α-halo aromatic amide carboxylic acid derivative according to claim 3, which is represented by formula 12. The α-haloaromatic amide carboxylic acid derivative according to claim 3, which is represented by the formula 13. The α-halo aromatic amide carboxylic acid derivative according to claim 3, which is represented by the formula 14. Formula 15 (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, and R1 and R2 are a halogen atom and a hydrogen atom, respectively, or are bonded to each other. (R3 is a hydrogen atom, a lower alkyl group, or a halogen atom) or a pharmaceutically acceptable salt thereof. . 16 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, R' is a halogen atom, R3 is a hydrogen atom or a lower alkyl group, and X is a halogen atom) 16. The antiallergic agent according to claim 15, which comprises an α-haloaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof. α- represented by the general formula 17 (Y in the formula may be the same or different, each is a hydroxyl group, a lower acyloxy group, or a lower alkoxyl group, R5 is a hydrogen atom or a lower alkyl group, and X is a halogen atom) The antiallergic agent according to claim 15, which comprises a haloaromatic amide carboxylic acid derivative or a pharmaceutically acceptable salt thereof.