JPH0564631B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides novel 4-thiazolidinone derivatives and salts thereof having antiallergic effects and tyrosine kinase inhibitory effects, and antiallergic agents and tyrosine kinase inhibitors containing the same as active ingredients. It is related to. (Prior Art) The compound according to the present invention is a novel compound that has not been described in any literature, and was synthesized for the first time by the present inventor. (Structure and Effects of the Invention) The novel compound according to the present invention is represented by the following general formula (1). {In the formula, R ¹ represents hydrogen, a C ₁ to C ₃ alkyl group, or a group represented by [Formula] (m represents 1 to 3), R ² represents [Formula] (n represents 1 to 4) and R ³ and R ⁴ are the same or different hydrogens or C ₁ to C ₃ alkyl groups. Also, R ¹ and R ² are bonded to each other to form −(CH ₂ )oX(CH ₂ )p
- [o, p represent the same or different 1 to 4,
X is an oxygen atom or N- ^R5 ( ^R5 is hydrogen or C1 _~
(represents a C ₃ alkyl group)]} The compound represented by the general formula (1) according to the present invention is:
It is possible to form a salt with a base, and the salt of the compound according to the present invention includes any salt that can be formed from the compound according to the present invention and a base. Specifically, for example, (1) metal salts, especially alkali metals,
Salts with alkaline earth metals, aluminum, (2) ammonium, (3) amine salts, especially methylamine, ethylamine, diethylamine, triethylamine,
There are salts with pyrrolidine, piperidine, morpholine, hexamethyleneimine, aniline, pyridine, etc. When using these salts as antiallergic agents or tyrosine kinase inhibitors, physiologically acceptable ones should be selected. Representative examples of the compounds according to the present invention are shown in Table 1. [Table] The compound represented by the general formula (1) of the present invention is synthesized by the following method. The method of ARARaouf et al.・Chimica Accademia Scientiarum Hungarica, Thomas [Acta Chim. (Budapest)], 87, 187
(1975)}, it can be synthesized by reacting with an amine represented by the general formula [Formula] (R ¹ and R ² are the same as above). The reaction temperature can be any temperature from 0°C to the boiling point of the solvent, but usually from room temperature to
A temperature of about 100°C is preferable. As the solvent used for the reaction,
Any of alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as dioxane and tetrahydrofuran; formamides such as N,N-dimethylformamide; and dimethyl sulfoxide can be selected. General formula (1) according to the present invention (wherein R ¹ and R ² are the same as above) The 4-thiazolinone derivative and its salt are effective as anti-allergic agents and tyrosine kinase inhibitors. Anti-allergic effect using guinea pig lung sections
SRS-A (slow reacting substance of
anaphylaxis) biosynthesis or release inhibition test. Eda et al.'s method [Journal of the Japanese Pharmacological Society, 66 , 194
(1970)] and the method of Kono-Watanabe et al. [J. Immunology,
125, 946 (1980)], the inhibitory effect on SRS-A biosynthesis or release was investigated. Hartley male guinea pig (weight 350-450)
g) were sensitized by injecting 1 ml each of ovalbumin solution (100 mg/ml) once into the buttock muscles and intraperitoneal cavity, and 4 weeks after the injection, they were killed by exsanguination, and immediately cold tyloid solution was injected through the right ventricle to inject the lungs. Perfused and blood removed. The lungs were cut into pieces less than 2 mm ² and 500 mg each was placed in each test tube containing 4.84 ml of Tyroid solution. Add 0.01 ml of the test compound dissolved in dimethyl sulfoxide (DMSO) to this, incubate at 37°C for 10 minutes, and add ovalbumin solution (10 mg/ml).
0.15 ml was added and incubated at 37°C for 20 minutes. As a control, DMSO was added and the reaction was carried out in the same manner.
After incubation, pass the reaction solution through gauze,
The amount of SRS-A in the sample was quantified. SRS-A was quantified by the Magnus method using guinea pig ileum. That is, the isolated guinea pig ileum (length: 2 to 3 cm) was suspended in a 10 ml Magnus tube filled with Tyroid solution (31°C, air aeration), and after the contraction response due to histamine (0.1 μg/ml) became constant. , SRS-A in the above reaction solution was measured in the presence of 1 μM atropine and 1 μM pyrilamine. Inhibition rate (%) is the contraction height by control 100
I asked for it as. As a result, it was found that the addition of 100 μM of the compounds shown in Table 1 suppressed the biosynthesis or release of SRS-A by 78%. Tyrosine kinase is known to be involved in the carcinogenic mechanism, and it has been suggested that tyrosine kinase inhibitors may be useful as anticancer or anticancer agents. The tyrosine kinase inhibitory effect of the compounds of the present invention can be determined by the tyrosine kinase activity assay method of S. Cohen et al. [The Journal of Biological Chemistry (J. Biol, Chem.), 257 , 1523 (1982)].
was measured using as a reference. Human cancer cell-derived strain A-431 was added to fetal bovine serum 10
%, streptomycin (50 μg/ml), penicillin G (50 international units/ml), and kanamycin (50 μg/ml) in Dulbecco's modified Eagle medium [Nissui Pharmaceutical Co., Ltd.] at 37°C and 5% CO ₂ conditions. cultivated under. The obtained cells were treated according to the method of Cohen et al. described above to obtain a membrane preparation containing the epidermal growth factor receptor-tyrosine kinase complex (hereinafter abbreviated as membrane preparation). This membrane preparation was used for the following measurements without solubilizing it. N-2-hydroxyethylpiperazine-
N'-2-ethanesulfonic acid buffer (20mM, PH
7.4), MnCl ₂ (1mM), bovine serum albumin (7.5μ
g) Add a sample dissolved in DMSO to a membrane preparation (10 μg as protein), incubate at 0°C for 5 minutes, add epidermal growth factor (hereinafter abbreviated as EGF) (100 ng), and incubate at 0°C. Incubated for 15 minutes. Next, [γ− ^32P ]ATP
(3000Ci/mmol, 0.1μCi), final 70μ
After further incubation at 0℃ for 15 minutes,
After impregnating 50μ of the reaction solution onto Watzmann 3MM filter paper, the reaction was immediately stopped with a 10% trichloroacetic acid-10mM sodium pyrophosphate aqueous solution. The filter paper was thoroughly washed with the same solution, then washed with ethanol, dried, and the radioactivity remaining on the filter paper was measured using a liquid scintillation counter, and this value was designated as A. At the same time, as controls, a reaction without the addition of EGF, a reaction without the addition of the sample, and a reaction without the addition of EGF and the sample were performed, and similar measurements were conducted, and these were designated as B, C, and D, respectively. The tyrosine kinase inhibition rate was determined by the following formula. Inhibition rate (%)=(CD)-(AB)/CD×100 The results are shown in Table 2. This result shows that the compound represented by general formula (1) of the present invention strongly inhibits tyrosine kinase. Note that the compound numbers correspond to the compound numbers in Table 1. [Table] Acute toxicity Using ICR female mice (body weight 23-26 g),
There were 6 animals in the group. Compounds () to () were suspended in a 2.5% gum arabic aqueous solution containing 0.2% Tween 80 and administered orally at a rate of 0.1 ml/10 g body weight. Observe general symptoms for two weeks after administration, calculate the number of deaths/tested cases, and determine the 50% lethal dose LD _50.
(mg/Kg) was estimated. As a result, no deaths were observed with the compounds () to () of the present invention even when administered at 1000 mg/Kg, and the LD ₅₀ of the compounds () to () was
It was estimated to be more than 1000mg/Kg, and was found to be of low toxicity. Preparation and Dosage The antiallergic agent or tyrosine kinase inhibitor according to the present invention may be prepared either by oral administration, enteral administration, or parenteral administration. Specific formulations include tablets, capsules, fine granules, syrups, suppositories, ointments, and injections. Carriers for the formulations of antiallergic agents or tyrosine kinase inhibitors according to the invention include organic or inorganic solid or liquid, usually inert pharmaceutical agents suitable for oral, enteral or other parenteral administration. A carrier material is used. Specifically, for example, crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc,
There are vegetable and animal fats and oils, gums, and polyalkylene glycols. The proportion of the antiallergic agent or tyrosine kinase inhibitor of the invention to the carrier in the formulation can vary between 0.2 and 100%. Furthermore, the anti-allergic agent or tyrosine kinase inhibitor according to the present invention may contain other anti-allergic agents, tyrosine kinase inhibitors, and other pharmaceuticals that are compatible therewith. In this case, it goes without saying that the antiallergic agent or tyrosine kinase inhibitor of the present invention does not need to be the main ingredient in the preparation. The antiallergic agent or tyrosine kinase inhibitor according to the invention is generally administered at a dosage that achieves the desired effect without side effects. The specific value should be determined by a doctor's judgment, but it is generally 10 mg to 10 g per day for adults, preferably
It would normally be administered in doses of about 20 mg to 5 g.
The antiallergic agent or tyrosine kinase inhibitor of the present invention can be administered as a pharmaceutical preparation containing 1 mg to 5 g, preferably 3 mg to 1 g, of the active ingredient. (Example) Next, the present invention will be specifically explained with reference to production examples of the compounds of the present invention, but these Examples are not intended to limit the present invention. Reference Example 5 - Production example of (3,5-diisopropyl-4-hydroxybenzylidene)-4-oxo-2-thionothiazolidine 4.12 g of 3,5-diisopropyl-4-hydroxybenzaldehyde and 2.67 g of rhodanine were mixed with 40 g of acetic acid.
ml, 3.32 g of sodium acetate was added, and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, the residue was dissolved in chloroform, washed with water, concentrated to dryness, and crystallized from toluene to give 5-(3,5-diisopropyl-4-hydroxybenzylidene)-4-oxo-
5 g of 2-thionothiazolidine (hereinafter referred to as compound A) was obtained. Example 1 Synthesis of compound 1.92 g of compound A obtained by the method of the reference example and N,N-
Dimethylethylenediamine 1.06g ethanol 50g
ml and heated under reflux for 8 hours. After cooling, the solvent was distilled off, the residue was dissolved in chloroform, washed with water, chloroform was distilled off, the residue was subjected to column chromatography using silica gel as a carrier, and eluted with chloroform to extract the fraction containing the target product. After concentrating to dryness, the compound was crystallized from ethyl acetate.
I got 1.5g. Example 2 Synthesis of compound 4.83g of compound A and 5.34g of N-benzyl-N',N'-dimethylethylenediamine were added to 100ml of ethanol.
The mixture was dissolved in water and heated under reflux for 6 hours. After cooling, the solvent was distilled off, the residue was dissolved in chloroform, and after washing with water,
Chloroform was distilled off, and the residue was subjected to column chromatography using silica gel as a carrier and eluted with chloroform. Fractions containing the target compound were concentrated to dryness and crystallized from ethyl acetate to obtain 2.30 g of the compound. Example 3 Synthesis of compound Compound A 1.93g and N-methylpiperazine 1.73g
was dissolved in 50 ml of ethanol and heated under reflux for 5 hours. After cooling, water was gradually added to the reaction solution, and the precipitated crystals were separated. Crystallization from ethanol yielded 1.7 g of the compound. Example 4 Synthesis of Compound 1.52 g of Compound A was dissolved in 40 ml of ethanol, 870 mg of morpholine was added, and the mixture was heated under reflux for 2 days. After cooling, the solvent was distilled off, chloroform and water were added to the residue, and the mixture was neutralized with 3N hydrochloric acid. Extract with chloroform,
The extract was concentrated and subjected to column chromatography using silica gel as a carrier, eluted with a mixed solvent of ethyl acetate-hexane (2:1, v/v), and the desired fraction was concentrated to dryness to remove the compound. I got 720 mg.

Claims (1)

[Scope of Claims] 1. A 4-thiazolinone derivative represented by the following general formula (1) and a salt thereof. {In the formula, R ¹ represents hydrogen, a C ₁ to C ₃ alkyl group, or a group represented by [Formula] (m represents 1 to 3), R ² represents [Formula] (n represents 1 to 4) and R ³ and R ⁴ are the same or different hydrogens or C ₁ to C ₃ alkyl groups. Also, R ¹ and R ² are bonded to each other to form −(CH ₂ )oX(CH ₂ )p
- [o, p represent the same or different 1 to 4,
X is an oxygen atom or N- ^R5 ( ^R5 is hydrogen or C1 _~
Represents a group represented by )] represents a C ₃ alkyl group. } Quadratic formula A 4-thiazolinone derivative and a salt thereof according to claim 1, which are represented by: cubic formula A 4-thiazolinone derivative and a salt thereof according to claim 1, which are represented by: Quaternary formula 4-thiazolidinone derivatives and salts thereof according to claim 1, which are represented by: Quintic formula 4-thiazolidinone derivatives and salts thereof according to claim 1, which are represented by: