JPS6172770A - Benzoxazine derivative - Google Patents

Abstract

NEW MATERIAL:2,2'-Phenylethenylidenebis(3,1-benzoxazin-4-one) shown by the formula I. USE:An antiallergic agent. PREPARATION:(a) 2,2'-[(1,3-Dioxo-2-phenylmetylene-1,3-propanediyl)diimino]- benzoic acid shown by the formula II is dehydrated in a nonaqueous solvent by heating preferably while distilling away water or by treating with a dehydrat ing agent, to give a compound shown by the formula I. Or, (b) 2,2'-methylene-bis (3,1-benzoxazin-4-one) shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] This invention provides bisbenzoxazine derivatives [namely, oxazine R] having immunomodulatory (antiallergic) activity.
The present invention relates to a method for producing the same and a medicine made from the same.

[Prior Art] Chlorpheniramine maleate, sodium cromoglycate, tranilast, and the like, which are conventionally known as anti-allergic agents, have had problems in terms of side effects, poor oral absorption, efficacy, and the like. The inventors previously discovered 2.2'-(
(1,3-dioxo-2-phenylmethylene-1,3-
Propanediyl)diimino]bisbenzoic acid was submitted (Japanese Patent Application No. 59-22360), but now it has been discovered that its dehydrated ring-closed product has a phase, and this invention has been completed.

[Structure of the invention]

3.1-Benzoxazine R is a compound represented by the following structural formula.

Compounds of formula CI) are prepared by the following method.

(a) A method comprising subjecting 2,2'-((1,3-dioxo-2-phenylmethylene-1,3-propanediyl)diimino]bisbenzoic acid represented by the formula to a dehydration reaction.

(b) A method comprising reacting 2,2'-methylenebis(3,l-benzoxazine) represented by the formula with benzaldehyde.

A more detailed explanation of these manufacturing methods is as follows.

[Method (a)]

The dehydration reaction is preferably carried out in a non-aqueous solvent by heating while distilling off water or by treating with a dehydrating agent. Examples of dehydrating agents include oxalyl chloride,
Organic or inorganic acid halides such as benzoyl chloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, organic or inorganic acid anhydrides such as trifluoroacetic anhydride, phosphoric anhydride, polyphosphoric acid, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N,N'-diisopropylcarbodiimide
”, N-ethylbenzisoxazolium salt, 2-chloro-1-methylpyridinium salt, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, dehydration condensation agents, regular sieves, etc. A desiccant is used. This reaction is usually carried out in a solvent such as benzene, toluene, dimethylformamide, methylene chloride, etc. The reaction temperature varies depending on the dehydrating agent used, but is usually room temperature or around the boiling point of the solvent. .

[Method (b)]

This reaction is carried out in the presence of a base or Lewis acid.

Lewis acids include BF3 (ether adduct), Ti
C1, ZrCl AA'CA'3, S n Cl 4
．． Z n Cl 2 or the like is used. This reaction is usually carried out in a solvent. As the solvent, xylene, toluene dioxane, dimethyl sulfoxide, etc. are used, and the reaction is usually carried out under heating. The raw material compound (I[[) is
2. Produced from 2'-[(1,3-dioxo-1,3-propanediyl)diimino]bisbenzoic acid in the same manner as method (a).

〔effect〕

Compounds of formula CI) have antiallergic action.

These compounds are thought to convert into compound (II) in the body, but they have better solubility, stability, and stability than compound (II).
It has excellent absorbency, and as a result shows excellent effects.

In the above applications, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment desired.

However, generally a dose of 1 to 6 mV/9, preferably 1
Satisfactory results are obtained when administered in divided doses two to four times a day or in the form of a sustained release formulation.

When administered for prophylactic and/or therapeutic purposes,
In the form of conventional pharmaceutical preparations containing the compounds of this invention as active ingredients, mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. can be administered. Such formulations can be solid, such as capsules, tablets, dragees, ointments, suppositories, or liquid, such as solutions, suspensions, emulsions. If necessary, auxiliaries, stabilizers, wetting agents, emulsifiers, buffers and other conventional additives can also be added to the above formulations.

〔Example〕

Hereinafter, this invention will be explained in more detail with reference to Examples and Test Examples.

Example 1 Compound (TI) 2. Of (4.65 mmol) is suspended in 200 mmol of dry benzene and 2.59 m/(18.60 mmol) of trifluoroacetic anhydride is added. When this suspension is stirred at room temperature, it will turn pale yellow to 1.
The result is a dark colored solution. After 1 hour, the solvent was distilled off and the residue was extracted with ethyl acetate. The organic layer was dissolved in IN, HC/, water, 4%
Washed sequentially with NaHCO3 and water and dried (MgSO4
), then the solvent is distilled off. The residue was crystallized by adding inpropyl ether to obtain a white solid of the target compound CI) at 1.67 g.
7 (yield 91%) is obtained.

mp: 214-215°C.

IR (KBr, cm-'): 1760 (C=O)I
I-1-NMR (CDCl2.δ): 8.33-7
．． 20 (m, aromatic hydrogen, vinyl hydrogen) Example 2 Compound (II) 4f (9,28 mmol) was suspended in 100 mm of dry benzene and cooled with oxalyl chloride 3.
2 ml (37.18 mmol) are added dropwise. Subsequently, 8 drops of dry DMF were added and stirred at room temperature for 2 hours. After the reaction, the solvent is distilled off and the residue is extracted with chloroform. Organic layer I
Washed sequentially with N-HC/, saturated saline, 4% NaHCO3 aqueous solution, and saturated, Japanese saline, and dried (Mg SO
4) Post-solvent distillation. The residue is dissolved in chloroform and adsorbed on silica gel, and column purification is performed (benzene: ethyl acetate = 4:1''). When crystallized from isopropyl ether, crystals of the target compound CI) are obtained.
6IC yield of 89%) is obtained.

The mp, IR, and NMR spectra completely matched those obtained in Example 1.

Example 3 2-chloro-N-methylpyridinium iodide 91 µ (2,78 mmol) was suspended in 5 d of dry methylene chloride under a N2 stream, and 500 mg of compound (If) (
1,16 mmol) and 0.76 i dry triethylamine
(5,57 mmol) dissolved in 5rnl of dry methylene chloride is added. Stirring is carried out at 40° C. for 3.5 hours. After the reaction, methylene chloride was added and IN-HC/, water,
After sequentially washing with a 4% Na HC03 aqueous solution and water and drying (MgSO4), the solvent was distilled off. The residue was crystallized with isopropyl ether to give 410 m crystals of the target compound (I).
9 (yield 9o%) is obtained.

The mp, IR, and NMR spectra completely matched those obtained in Example 1.

Example 4 Compound (II) 500 mg (1.16 mmol) and 4
-Dimethylaminopyridine 28"9 (0.23 mmol) was suspended in 10 rnl of dry methylene chloride, and dicyclohexylcarbodiimide 605 m'1 (2
, 781 mol). Stirring is carried out at 40° C. for 3.5 hours. After the reaction, insoluble matter was removed, methylene chloride was added to the p solution, and 1N, HCl! , water, 496N a HCO3
It is washed successively with an aqueous solution and water, dried (MgSO4), and then the solvent is distilled off. The residue is crystallized from isopropyl ether to obtain 415 m'i of crystals of the target compound (I) (yield: 91%).

The mp, IR, and NMR spectra completely matched those obtained in Example 1.

In Example 2, the reaction was carried out in benzene at room temperature for 2 hours using thionyl chloride instead of oxalyl chloride, or the reaction was carried out in benzene at 80°C for 2 hours using phosphorus oxychloride, or Even when the reaction in Example 4 was carried out in tetrahydrofuran at room temperature for 2 hours using N,N'-carbonyldiimidazole in place of itedicyclohexylcarbodiimide, the target compound CI) was similarly obtained in high yield. .

Example 5 Benzaldehyde 259-(2,45 mmol), Compound (II[) 500 μ(1,63 mmol) and B
F3 ・ (C2H5)20 0.0 4 5 m
A' (0,163 mmol) in dry toluene 20
Heat to reflux in ml for 20 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, extracted with benzene, and the organic layer was separated, washed with water, and dried (MgSO4).
The solvent is distilled off under reduced pressure, the residue is dissolved in a developing solvent, adsorbed on silica gel, and purified by column chromatography to obtain the target compound (I). This is crystallized using isopropyl ether to obtain the target compound (I) as a white solid in good yield.

The mp, IR, and NMR spectra completely matched those obtained in Example 1.

1 Example 6 (1) Compound CI) 25.0
0-(2) Lactose 49.0
0rng crystalline cellulose 36.00
■Corn starch 5,00~
(3) Hydroxypropyl cellulose 1゜oo
q(4)ECC, 505 (carboxymethylcellulose calcium') 2. OOm? (5) Magnesium stearate 1.00”?(6
) Talc 1. OO
"+7 total 120rI1g (1) + (21 was kneaded with 596 aqueous solution of (3), dried, sized, mixed with (4), (5), and (6), and compressed into 120"7 tablets. (φ7m) I to make a tablet.

Example 7 (1) Compound (1) 50.
00ki (2) Lactose 124
．． 50η(3) Cornstarch 2
0.00”7(4) Hydroxypropylcellulose
2.00”1(5) Light silicic anhydride
1.50m'J (6) Magnesium stearate 2. OOm? Total of 200 m7 tl) + (21+ +31 was kneaded with a 5% aqueous solution of (4), dried and sized, and (5) and (6) were added and mixed.
Fill a No. 3 hard capsule with 200 μg.

Test Example 1 Anti-passive cutaneous anaphylaxis (PCA) in rats
Effect (test method) Wistar rats were sensitized in advance with ovalbumin using aluminum hydroxide gel and pertussis vaccine as an adjuvant, and blood was collected 14 days later to obtain diluted antisera (16x and 32x). ) was administered to the dorsal skin of syngeneic rats at 0.1 doses per site and kept for 48 hours.

One hour after the oral administration of the sample solution, a mixture of the antigen ovalbumin and the dye Evans blue was administered into the tail vein according to a conventional method. After 30 minutes, the animals were exsanguinated to death and the blue inflammation at the dorsal antiserum injection site was investigated. The area (major axis x minor axis) was determined, and the inhibition rate was determined based on the average shown by the control group animals.

(Results) Anti-PCA action compound (1) was found to have anti-PCA action upon oral administration, and was found to be stronger than the controls tranilast and sodium cromoglycate.

Test Example 2 Effect of suppressing histamine release from rat intraperitoneal mast cells The effect of suppressing histamine release from mast cells by antigen-antibody reaction was investigated.

(Preparation of DNP-Ascaris antiserum) Pig reincarnation extract was converted to DNP by Eisen's method, dialyzed and lyophilized, and administered subcutaneously to rat footprints together with pertussis vaccine as an antigen. After 8 days, blood was collected and used as antiserum. . The PCA titer of this antiserum in rats was 32-64.

(Collection of intraperitoneal mast cells and cell sensitization method) Heha lJ
After injecting PBS containing PBS into the peritoneal cavity of a rat that had been sacrificed by exsanguination, the injected PBS was collected by thoroughly shaving the abdomen, and was washed and purified several times by centrifugation. The number of mast cells contained in this solution was measured and adjusted to a predetermined concentration. The cell sensitization method is to add anti-DNP-Ascaris rat serum (PC
A titer 32 > 6- was added to 37 in the presence of heparin.
It was incubated at ℃ for 2 hours.

1 (Quantification of free histamine) After adding the test drug solution to the sensitized mast cell suspension and preliminarily incubating at 37°C for 12 minutes, the antigen DN
A P-Ascaris (final concentration 20 μH/mt) solution was added and further incubated for 20 minutes. After the reaction is complete, centrifuge at low temperature (500G, 10 minutes) to obtain the supernatant.
Histamine in the supernatant was quantified by fluorescence using the orthophthalaldehyde method.

(Results) Amount of histamine released from intraperitoneal mast cells (control = 100) Compound 10' 1010-510-410-3 (Tranilast 95 95 67 29 Compound (I) 70 68 60 21 (DN P
- Ascaris (antigen) final concentration 20 μg% n/) Compound (1) was found to inhibit the release of histamine from mast cells even at a low concentration of io-'5 M.
It showed a stronger inhibitory effect than the control tranilast in the range of 10-3 to I.

Test example 3 acute toxicity (Test method) ICR mice (male) were used as animals.

A suspension or solution of the sample was administered to animals according to a conventional method, and the L D so value was determined by the probit method from the number of deaths within one week after administration.

(Results) As shown in the compound L Dso value table, the D5o value of compound (1) was 1.
0! /Ky or more, and 319 m/Ky for intravenous injection.
KSI and was found to have extremely low toxicity.

Claims (3)

[Claims] (1) 2,2'-phenylethenylidene bis(3,1-
benzoxazin-4-one) (2) 2,2'-phenylethenylidene bis(3,1-
An anti-allergic agent containing benzoxazin-4-one as an active ingredient. (3) (a) 2,2'-[(1,3-dioxo-2-phenylmethylene-1,3-propanediyl)diimino]
Bisbenzoic acid is subjected to a dehydration reaction, or (b) 2,2
A method for producing 2,2'-phenylethenylidene bis(3,1-benzoxazin-4-one), which comprises reacting '-methylenebis(3,1-benzoxazin-4-one) with benzaldehyde.