JPS5824519A - Antiallergic - Google Patents

Abstract

PURPOSE:An antiallergic that contains a cyclic compound crosslinked with a specific double bond, as an active ingredient, thus being effective as a preventive and remedy for bronchial asthma and allergic rhinitis. CONSTITUTION:The objective antiallergic contains a compound of formulaIor II[X is CH, N; Y is (CH2)n (n is 0, 1), CH=CH, N-alkyl, blank; R1, R2 are alkyl, allyl, cycloalkyl, heterocyclic ring; R3 is H, alkyl, aralkyl, cycloalkyl]as an active ingredient. This active ingredient inhibits the liberation of chemotransmitters from mastocytes or basophilic leukocytes to develop antiallergic activity. Some of compounds of formulaIand II are novel.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-allergy crosslinker containing a double bond-crosslinked cyclic compound represented by the general formula % or a salt thereof as an active ingredient. In addition, each symbol in Formula 9 has the following meaning.

X: CH or N Y: (CHz)n (n is 0 or 1), CH=CH
,O.

N-alkyl or blank R1 and R2: alkyl, allyl, cycloalkyl.

or heterocycle R3: H, alkyl, aralkyl, or cycloalalkyl. These compounds are known or new compounds.

The known one is German Patent No. 2,027,446 (197
1) and Chem, Pharm, Bull,...
27.2061 (1979). Examples of methods for producing these compounds are shown below.

Example 1 1-benzyl-4-diphenylmethylidenepiperidine (
Formula I: R1, R2=phenyl, R3=benzyl,
X=N.

Production of Y=blank): To a solution of 0.5 g of magnesium in 100 ml of anhydrous ether, 15 g of benzyl bromide was added to 150 ml of anhydrous ether.
A solution dissolved in was added dropwise, and the mixture was heated under reflux for 1 hour. A solution of 9.3 g of l-benzyl-4-piperidic acid ethyl ester in anhydrous ether was added dropwise to this mixture under water cooling, and the mixture was heated under reflux for 1 hour, then made alkaline with 10% potassium hydroxide and extracted with ether. After washing the ether layer with water and drying, the solvent was distilled off, the residue was separated by elution chromatography using alumina, and the obtained crystals were recrystallized from cyclohexane to give (1
5.4 g of -benzyl-4-piperidinyl)diphenylmethanol were obtained.

5.4 g of this product was added to 20 ml of 20% sulfuric acid, heated under reflux for 1 hour, and then made alkaline with 10% potassium hydroxide and extracted with ether. After washing the ether layer with water and drying, the residue obtained by distilling off the ether was recrystallized from dichloromethane to obtain 2.8 g of 1-benzyl-4-diphenylmethylenepiperidine having a melting point of 90-92°.

Example 2 1-benzyl-4-fluorenylidenepiperidine (formula 1
: RI, R2-phenyl, R3-benzyl, X
=N.

Production of Y=(CH2)0) 12 g of 1-benzyl-4-chloropiperidine was added dropwise to a solution of 30 ml of anhydrous tetrahydrofuran to which 1.6 g of magnesium had been added, and the mixture was heated under reflux for 2 hours.

A solution of 11 g of 9-fluorenone dissolved in 20 ml of anhydrous tetrahydrofuran was added dropwise to this mixture under water cooling, and after heating under reflux for an additional 2 hours, the solvent was distilled off under reduced pressure.

An aqueous ammonium chloride solution was added to the residue, extracted with ether, the ether layer was extracted with 20% hydrochloric acid, and the hydrochloric acid solution was heated in a water bath for 2 hours. After cooling, the mixture was made alkaline with ammonium chloride and extracted with ether, and the ether layer was washed with water and dried.

The solvent was distilled off and the residue was recrystallized from ether to give mp11
10 g of 4-115' 1-benzyl-4-fluorenylidenepiperidine was obtained.

Example 3 Preparation of 1-benzyl-4-(4-isochromanilidene)piperidine (formula II: Rs=benzyl, X=N): 17.6 g of homophthalic acid diethyl ester
3.6 g of 50% sodium hydride was added to the solution and stirred at room temperature for 30 minutes. A solution of 14 g of 4-benzylpiperidone dissolved in 200 ml of anhydrous benzene was added dropwise to this mixture at room temperature, and the mixture was further stirred at room temperature for 5 hours. Benzene was distilled off under reduced pressure, and 150 ml of absolute ethanol was added to the residue, and the mixture was heated under reflux for 10 hours while passing dry hydrogen chloride through the mixture. The ethanol was distilled off under reduced pressure, and the residue was made alkaline with 10% potassium hydroxide and extracted with ether. After washing the ether layer with water and drying, the ether was distilled off and the resulting residue was separated and purified by elution chromatography using alumina to obtain α-(1-
26 g of benzyl-4-piperidinyl)homophthalic acid diethyl ester was obtained.

Dissolve 25 g of this in 20 ml of anhydrous ether.

3 g of lithium aluminum hydride to 100 g of anhydrous ether
It was added dropwise to the solution dissolved in ml under cooling. then 6
After heating under reflux for a period of time, excess lithium aluminum hydride was decomposed with water, made alkaline with 10% potassium hydroxide, and extracted with ether. After washing the ether layer with water and drying,
The residue obtained by distilling off the ether was separated and purified by elution chromatography using alumina.

Colorless essential oil of α-(1-benzyl-4-piperidinyl)-2-hydroxymethylphenethyl alcohol 2
Obtained 0g.

Put IOg of this into a Soxhlet apparatus, dissolve 100ml of benzea, and 7.6ml of P-toluenesulfonic acid.
g was added thereto, and the mixture was heated to reflux. Anhydrous magnesium sulfate was added to the thimble filter paper, and the mixture was allowed to react for 2 hours while absorbing moisture, and then made alkaline with 10% potassium hydroxide and extracted with ether. Wash the ether layer with water.

After drying, the residue obtained by distilling off the ether was separated and purified by elution chromatography using alumina, and 1-benzyl-4-
5 g of a colorless viscous oil of fluorenylidene piperidine was obtained.

The present invention discloses that the above-mentioned double-bonded cyclic compounds are chemical messengers (histamine, serotonin) from mast cells or basophils during allergies.

5R8-A, etc.) and exhibited antiallergic effects. Sodium chromoglycate (DSCG), which has a chromone skeleton, is a compound that suppresses the release of chemical mediators, but such an effect is not yet known for cyclic compounds with double bonds. However, only a few are known to have antihistamine effects. Anti-allergic drugs that suppress the release of chemical substances are immediate-acting.

It is also effective as a prophylactic and therapeutic drug for allergies called type I, such as bronchial asthma and allergic rhinitis.

The test method and effect of the antiallergic effect of the present invention will be explained in detail below.

Mast cells are thought to be necessary for pharmacological evaluation of drugs that suppress the release of chemical mediators.

Effect of suppressing histamine release Inhibition of histamine release from isolated rat mast cells - Wistar rats weighing 200 to 350 g were hit on the head to cause fainting, and then killed by bleeding from the common carotid artery.
15 ml of a physiological saline solution (hereinafter referred to as PS solution) infused with 5% CO2 and 5% CO2 was injected intraperitoneally, and the abdominal wall was gently massaged for 2 minutes. Thereafter, a small incision was made in the abdominal wall to collect ascites fluid, which was centrifuged at 500 rpm for 5 minutes at 4°C. The precipitate was suspended in an ice-cold PS solution.

It was centrifuged under the same conditions. The mast cells in the sediment were suspended in an appropriate amount of PS solution and used for the experiment.

1.9 ml of PS solution in which mast cells (1 to 2 x 10 cells) were suspended was placed in a centrifuge tube and incubated in a thermostat at 37°C for 5 minutes. For this reason, we divided them into two groups, one group was used as a control, and the mast cell suspension of the other group was treated with Compound 48/80 (We-11c).
ome Reagents Ltd, Br1t, J
, Pharmacol.

(1951), 6, 499; o,s ~5μg/
ml), 0.1 ml and further incubated at 37°C for 15 minutes.
Incubated for minutes. For control, PS solution 0.1 m
1 was added and incubated in the same manner. Thereafter, the reaction was stopped by cooling the centrifuge tube on ice, and the tube was incubated at 4°C and 1500 rpm for 10
Separate the supernatant by centrifuging for minutes, and add fresh PS solution 2 to the sediment.
ml was added to suspend the cells. 0.05 ml of IN hydrochloric acid was added to both the supernatant and the cell suspension, and the samples were immersed in a boiling water bath for 5 minutes. Test drug compound 48
In an experiment to investigate the inhibitory effect of 48/80 on histamine release, various concentrations of the test drug were added to the PS solution after the brain incubation and allowed to act for 15 minutes, and then Compound 48/80 was allowed to act in the same manner as before. We investigated its effectiveness. In the control group, Compound 48/80 was not applied, and other operations were performed in the same manner to prepare samples for measuring the amount of histamine contained in the supernatant and sediment.

Histamine was quantified using the 5hare fluorescence assay method (J.

Pharmac, exp, Ther, 127182~
186 (1959)). That is, 0.4 ml of IN sodium hydroxide solution and 1
Add 0.1 ml of 96o-phthalaldehyde solution, stir, and react at room temperature for 4 minutes, then add 0.2 ml of 2M citric acid.
1 was added to stop the reaction, and the fluorescence intensity was measured at an excitation wavelength of 360 nm and a fluorescence wavelength of 440 nm, and the histamine concentration of the sample was determined from a separately prepared calibration curve. The calibration curve is
It was prepared every time histamine was quantified.

The histamine release rate was calculated using the 9th order equation.

Hr: amount of histamine released in the sediment Hp: amount of histamine remaining in the sediment The inhibition rate of histamine release when the test drug was applied was calculated using the 9th equation.

Inhibition rate = 2 x 100 A: Histamine release rate when Compound 48/80 acts alone B: Histamine release rate when Compound 48/80 acts in the device with the test drug Obtained in this way Table 1 shows the inhibitory effect on histamine release.
Shown below.

Table 1 = Histamine release inhibitory effect Note 20, Concentration of each compound required to inhibit 50% of histamine release promoted by Compound 48/80 at a concentration of 5μ97ml

Claims (1)

[Claims] I II (wherein, X represents CH or N, Y means (CH2)n (n is 0 or 1), CH=CH, 0,N-alkyl, or blank, R+ and R2 each mean an alkyl, allyl, cycloalkyl, or heterocyclic group, and R3 means an H, alkyl, aralkyl, or cycloalalkyl group). An anti-allergy rack containing a cyclic compound or its acid addition salt as an active ingredient.