JPS6084217A - Antiallergic agent - Google Patents

Abstract

PURPOSE:An antiallergic agent, consisting of 2-(bromodifluoromethylmercapto) anisole, capable of keeping the strong and selective antagonistic action on slow-reacting substances of anaphylaxis (SRS-A), and useful as a remedy for bronchial asthma, etc. with low toxicity. CONSTITUTION:An antiallergic agent consisting of 2-(bromodifluoromethylmercapto)anisole of the formula. The compound of the formula is well known as an intermediate for a remedy for hypocholesterolemia, germicide, etc. but newly found to be useful as an antiallergic agent. The compound of the formula has strong and selective antagonistic action on slow-reacting substances of anaphylaxis (SRS-A) and useful for preventing and treating various allergies, e.g. bronchial asthma, allergic rhinitis or urticaria, caused by the SRS-A. The SRS-A is considered to be particularly a causative substance for the bronchial asthma, and therefore expectable as a specific medicine for the bronchial asthma.

Description

[Detailed description of the invention] The present invention relates to a novel antiallergic agent.

More particularly, the present invention provides 2-(bromodifluoromethylmercap b' having the formula
) 7-'-So 11z7'n P KaX r#"7
1/ll7M *+l t-TUI −+ X.

The antiallergic agent of the present invention is 5R3-A (slowre
actlng 5ubStance of anaph
ylaxis) caused diseases, such as Qi? 6., bronchus,
It is useful as a therapeutic agent for allergic diseases of the lungs 1, allergic rhinitis, allergic eczema, hay fever, etc.

Anaphylactic allergic reactions, which are one type of allergic reactions, can be divided into three stages. The first stage is the process in which reagin produced by the antibody-producing cell line adheres to mast cells and basal cells in the tissue and sensitization is established, and the second stage is the process in which reagin on the cell surface -I- The fifth step is the process in which chemical mediators are released from cells in response to allergens; the chemical mediator increases capillary permeability, contraction of the tunicus muscle, secretion of airway 17 smooth muscle mucus, and airway mucosal secretion. This is the process in which edema etc. develop.

Chemical mediators released in the first stage of 1- are histamine, 5R3-A, serotonin, prostaglandin, thromboxane A-, bradykinin, ECF-A.
-1NCF, PAFJ are currently known, and in anafraquine-type allergy, especially histamine and 5R
5-A is the construction cost.

Research on the substance and pharmacology of 5R3-A has recently made rapid progress, and it has been revealed that SRS-A is a group of arachidonic acid metabolites composed of leukotrienes. Therefore, the pharmacological properties of SR3-A are understood as those of leukotriene m.

The pharmacological properties of 5R3-A include contraction of guinea pig ileal smooth muscle, contraction of bronchial smooth muscle, and enhancement of vascular permeability.
Leukotriene C4 (LT) is considered to be the main body of RS-A.
It is known that C4) and U O (Dl・Lien D (LTD) are histamine c7) 11000 (J, 'f: 4 times) showing a strong constrictive effect. From these facts, 5R3-A is known to be effective against bronchial asthma. It is thought to be the causative agent of various types of anaphylaxis, such as allergic rhinitis and hives.

Therefore, in the fifth stage of allergy development mentioned above, S f
l A drug that suppresses the pharmacological action of S-A, i.e., 5R5
-A antagonists are expected to be useful antiallergic agents.

However, there are few drugs that antagonize 5R3-A, and to date, no examples of practical use have been reported. FPL-55712 (7-(3
-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2- and I.roxypropoxy)-4-oxo-8-propyl-4H-1-hengo-nohyrano-2-carboxylic acid sthorium salt] This drug has been widely studied and has a very strong S, R3
-A #iL effect [Nature
) 2454215 pages (+873 't')'). However, this substance is rapidly converted and opened in vivo [Agent
ts and Actions), tf'r vol. 9, p. 133 (1979)] There is no money to use it.

The present invention was completed by Nagisa et al. as a result of their search for an antiallergic agent that is antagonistic to 5R3-A. l.) An anti-allergic agent consisting of anisole.

Compounds of the present invention [I''J is special υ] 11 not 57 8
It is a known compound described in No. 0366 and is known to be useful as an intermediate for various physiologically active substances such as a therapeutic agent for hypocholesterolemia and a bactericidal agent. However, to date, it has not been described or shown in the literature that the present compound CI) or its analogues have an antiallergic effect.

The compound CI) of the present invention is, for example,
According to the method described in 0366 Hibiki Specification Example 12 -cO
-Produced by reacting methoxythiophenol with i.lium hydride in dimethylformamide and then reacting the reaction product with bromochlorodifluoromethane.

The compound CI) of the present invention is useful for the prevention and treatment of various allergic diseases caused by 5R3-A, such as bronchial asthma, allergic rhinitis, and hives. As shown later in the test examples, it exhibits a strong and selective 5R3-A antagonistic effect, has low toxicity, and maintains effective activity even in the body.

That is, the compound CI) of the present invention is obtained from isolated guinea pigs.

IIV k by 5R3-A in 11M for 1-1,
50% reduction at 0.5 mc4/m1 concentration; ljj L
, Taikihistayu..., serotonin, and acetylcholine-induced lees collection by 25% and IO of 150mcg/ml concentration, respectively, are suppressed by 80%. The present compound CI) exhibits a strong antagonistic effect on 5R3-A, 4'+' It does not show strong antagonism with. As mentioned in 11J, 5R3-A is a bronchial asthma report.

Since the compound [I] of the present invention is considered to be a causative agent of It is expected to be a special drug for asthma. It was also confirmed through in vivo experiments that the uninvented compound CI) inhibits the contraction of bronchial smooth muscle caused by allergic reactions.

The administration form of the compound of the present invention (CI) is parenteral administration in the form of 4-dose drugs (subcutaneous, intravenous, intramuscular, I+! intracavitary injection), softeners, suppositories, airsols, tablets, capsules, etc. , granules, emulsions, syrups, powders, liquids, emulsions, suspensions
Oral [T administration with drug A, etc. can be avoided.

The clinical importance of the compound (1) of the present invention may vary depending on the age, body temperature, sensitivity of the person, symptoms, etc., and the usually effective administration h1 is as follows: Adult-t-10,
02 to 1.5 g, preferably about 0.05 to 0.9 g. However, if necessary, you can also use the stars outside of my area.

The uninvented compound is thrown into the river and formulated by conventional pharmaceutical means.

Tablets, capsules, granules, and emulsions contain excipients such as sucrose, lactose, grape S, starch, mannin, binders such as syrup, gum arahia, seratin, and turmeric. , I. Lagant 1. Notylcellulose, polyvinylpyrrolitone; disintegrants such as starch, carboxydimethylcellulose or its calcium salts, microcrystalline cellulose, polyethylene glycol, lubricants such as talc, magnesium or calcium stearate, silica: 18A? rFJ 611
', for example, prepared using sodium laurate, chrycerol, etc. l): Shoots, solutions, emulsions, suspensions, syrups and aerosols contain a solvent for the active ingredient, such as water, ethyl alcohol, inopropyl alcohol, propylene glycol, 1,3-methylene glycol, polyethylene glycol, Surfactants, such as sorbita 7 fat It/j acid ester, polyoxyethyl acid ester, Lechtan fat 1f/j m ester, polyoxyethylene fatty acid ester, hydrogenated castor oil fl,) oxyethylene ether, lecithin: Coconut, 7%i11.1 List of Calhoyan Methyl Sodium j) Ingredients, cellulose conductors such as methyl cellulose, I. Lakano'I.1 Alahiakom't's natural products 1, class; preservatives, e.g. roseoxy' The ester of tetrazoic acid, penzarkonium 14ide, is prepared using norhinate mounds. Suppositories are prepared using, for example, polyethylene glycol, lanolin, cocotin 1-oil, and the like.

Next, the present invention will be explained in more detail by showing production examples, test examples, and examples.

2-(bromodifluoromethylmercapto) Sodium A hydride (50%+noil,
1.4g, 29mmol) in dimethylformamide (
The solution was distilled from calcium hydroxide, suspended in 20 ml of water, and cooled in a water bath.

While thoroughly stirring with a stirrer, a solution of 0-methoxythousenol (4,0 g, 28,5 mmol, l) in dimethylformamide (same as above, 40 ml) was slowly added dropwise. Continue stirring for an additional 10 to 20 minutes to complete foaming. This is cooled to -78°C in a triice-acetone bath. Add dibromodifluoromethane (log, 47.7 mmol) while stirring well.
) in dimethylformamide (120ml) is added as quickly as possible using a syringe. The reaction ends almost instantly. Slowly bring the temperature of the reaction solution back to room temperature and place it in ice water. Extract with methylene chloride several times, wash the extract with brine, and then dry over anhydrous magnesium sulfate. After removing the solvent using a rotary evaporator, 63g of the 14-sized product was obtained by vacuum distillation.

Yield: J, (83% boiling point 74-77℃/O, 15m
mHg Test Example 1 The antagonistic effect of the compound (I) of the present invention against 5R3-A was determined using a guinea pig ileal smooth muscle specimen.

Evaluation of 5R3-A antagonism is shown in Tab 1.

Ross et al. (J, W., Ross et al.) (1
st Arcks A! lergy A, ppl, 1m
mun, 5121f (-237,19-/8) (1)
I apologized to the Kahu people.

Wistar M1 rats (250-300 g) sensitized with ovalbumin were exsanguinated to death, intraperitoneal I/M was collected, centrifuged for 1 minute, and the human fluid was used as a 5R3-A solution. The compound [1] of the present invention was injected into the isolated Mormont ileum, and after 30 seconds, 1 fl of the 5R3-A solution described in 1 was prepared, and the contraction of the ileum was measured by the Magnus method. The inhibitory concentration of the compound of the present invention was determined. Above 5
Since the R3-A solution also contains heptarotonin and histamine, in order to eliminate the contractions caused by these, the R3-A solution was treated in the presence of their antagonists atropine (0.16 mcg/ml) and mepyramine (0.8 + ncg/ml). So 5R3
- A8 static was applied.

In addition, the antagonistic effects of the compounds of the present invention on histamine, serotonin, and acetylcholine were similarly measured using guinea pig ileum17. Histamine (0゜5mcg/ml)
, Serotony' (1 m+4/ml), ``The concentration of the compound (I) of the present invention was determined to inhibit 80% of the contraction that occurs when acetylcholine (0.1 mcg/ml) is applied. The results are shown in Table 1.

From Table 1, the compound [I] of the present invention has a 1-
It is clear that they have a strong antagonistic effect and that this effect is selective.

Test Example 2 (Experimental method) ■) Anti-dinitrophenylated Ascaris extract (DNP
-A'S) The prepared antiserum of Ramenjisei is multi(1)
method (The Journal of Immun
ology, vol, 106. No, 4.1002
2.0 of the extract of Ascaris 5uu ID prepared according to ~+1 (,'71) with a dinitrophenyl group attached (DNPA S ).
mg (as protein) 0? x10 White 14 Killed Bord
etella Pertussis ) and 4 Ashikaga and 0
．． 5 meters! After binding and dividing into 4 parts, the mixture was injected into the f wrinkles of one (Sufu-type #I; sex runt (180-200 g of body hair)). After 51 days, 5 mg of DNP-As was injected intramuscularly into the back for additional stimulation. Eight days after the initial viscosity f1, a section was taken from the I11 artery under ether anesthesia, and the antiserum was separated. Antiserum was stored frozen at -20°C. The titer of the anti-+m serum was measured by a 48-hour allogeneic PCA foot counting method, and those with a titer of 128 and 256 times were used for the experiment.

2) Suppression of airway contraction Body weight 340.4 ±I O, O'g Wistar system) J
Anti-DNP-As runt serum 20ml per animal
1 was injected intravenously through the tail vein. 24 hours later, 50 mg/kg of culinobarbital sodium salt was injected intraperitoneally.
The rat was fixed on the back 4Jt in an anesthetized chamber, the trachea was exposed, and a human
A tracheal cannula connected to the breathing circuit was inserted. Also, the big Ill on the right side! An arterial cannula was inserted into the Il artery, and the resting pressure was measured via a pressure transducer (Hhonkoden, MPU-05). Heart rate is instantaneous heart rate 1,1
411 was set by the unit, and experimental conditions were set that did not significantly affect Jr11 pressure and heart rate. Decamethonium bromide 0.34 mg/min i, v, continuous infusion.
, load pressure 8 cmH20, air supply M5-7 ml/time).

Inhalation application of DNP-As was carried out for 10 minutes after 20 minutes of intraperitoneal administration of the drug or solvent using an ultrasonic skin nebulizer installed in the person's breathing circuit. In addition, for melting y, 0.3% Tween 80 (Atlas Paraturn 1
DNP-A in Nayanpa
The S solution was 6 mg Protea/ml, and the volume of the Kublyzer was adjusted so that the drug consumption 11 per inhalation application was 0.5 ml.

and 1 respiratory circuit tract 1. A passage opened to the outside air is cut through the passage, and an air pipe overflows through this passage.
Regarding the change in 1 as a change in road A resistance, S, L 4F3
The degree of contraction of the q' smooth muscle was expressed as ΔIll 'ji:'. The overflowing air J11 is the Konzett-Ross
By ler method conversion, call':j m 'l',' ii
-I using 1 (1-1 Photoden, AF'-620G)
II 'iif L, further integrating preamplifier (1:I
Amplified and recorded using EI-6θOG).

(Experimental Results) Inhalation of 3 mg of DNP-As (protein) was found to increase airway resistance. That is, allergic airway constriction was observed due to DNP-As. -1 of airway resistance
It started occurring 1 to 2 minutes after the start of inhalation, and showed an increase of about 75% after 10 minutes of inhalation. After the end of inhalation, there was a gradual recovery trend, but even after 30 minutes, a 25% increase was observed compared to before inhalation.

Compound (I) of the present invention 10mg/kg was added to DNP-As
DNP-A by intraperitoneal injection administration to inhaled HiJ
Significant contraction suppression was observed 5 minutes after the start of inhalation of S, and the contraction was suppressed by about 40% after 1' of the inhalation route. In addition, the compound of the present invention (
1) 30 mg/kg intraperitoneal 11-premortem treatment,
Significant contraction suppression was observed 5 minutes after the start of inhalation, 10 minutes after the start of inhalation, and 5 minutes after the start of inhalation.

1. The results are shown in the drawing.

Test Example 3 Using ddY dead-headed mice (4 years old), 11 intracavity tests 1
LD5o of the compound of the present invention in j- and [I-throwing]
I got the price.

11u intracavitary injection Jj-L D 1091.2 (826,7
-1440,4) 50 mg/kg - Bun ih Kamii row 1 Tablet, +, Invention compound (I) log Milk 11'f 2 + - J g Starch 4g Starch (Norikawa) 1g Selmy Scarcilla 1\ All 'I', 42, J, g l- listed ingredients are combined in a conventional manner to give 50% in one tablet.
It was made into a nII-coated tablet containing mg of the zl ingredient.

Example 2 Capsules, 4. , light 1jll compound (1) Log lactose 20g microcrystalline cellulose LOg stearin], g Magnesium total 1 is 4.1 g After blending the above ingredients in a conventional manner, fill them into gelatin capsules, and add 5Qmg of activity in the I capsule. It was made into capsules containing the ingredients.

Example 3 Soft capsules Compound (I) of the present invention log Corn oil 35g Extra: 45g 1: The ingredients listed above were combined and then made into soft capsules by a conventional method.

Example 4 Soft・^ Compound of the present invention [:I) 1.0g Master 1 - 7 mountains 20g White petrolatum 79g Total amount 100g '' - The ingredients listed above were mixed in a conventional manner to form a 1% ointment.

Example 5 Eanl Suspension Solution (A) Compound of the Invention [I] 0.25% Mi 1) Stinchu 0.10 Isopropylec, Nord 2640 (B) 40% 41 compound 73.25 Composition 1 Mix (A) in I2, and charge the resulting IF+a mixture into a container.
! 14 agents (131 to 20'c (glue 2.46 to 2.81
kg/cmL (KJ W'l, etc.) 7 months since Harunnosuru.

[Brief explanation of drawings]

The figure is a graph showing changes in airway smooth muscle contraction. In the graph, the vertical axis shows the overflowed air volume (ml), and the horizontal axis shows the elapsed time (minutes) after DNP-As inhalation. In the graph, (1) shows the case where Con I roll, (2) shows the case where 10 mg/kg of the compound of the present invention (CI) was administered, and (3) shows the case where the undeveloped compound (1) was administered at 30 mg/kg. .

Claims (1)

[Scope of Claims] An antiallergic agent comprising 2-(70modifluoromethylmercapto)anisole having the formula