JPH07252294A - Adrenocortical steroid derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound excellent in water solubility, having antiallergic activity, anti-inflammatory activity and antioxidizing activity, etc., thus useful for preventing or treating allergic diseases, inflammatory diseases, cataract and ischemic organopathy. CONSTITUTION:The objective compound is expressed by formula I (R is H, OH, methyl or methylene; however, when there is OH at the 17-site of the steroid skeleton, or when R is OH, also including the acylated form or ketone form of the steroid skeleton, respectively) or a salt thereof, e.g. 21-(L-ascorbic acid-2-phosphoryl)dexamethasone sodium salt. This compound of formula I can be obtained by condensation reaction between an adrenocortical steroid of formula II and ascorbic acid-2-phosphoric ester of formula III in the presence of a dehydrating condensation agent (pref. N,N'-dicyclohexylcarbodiimide) in a solvent (pref. pyridine) at room temperature for 1-5hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel and useful corticosteroid derivative, a method for producing the same, and a preparation containing them. More specifically, the present invention provides 21-
The present invention relates to (ascorbic acid-2-phosphoryl) corticosteroid, a pharmacologically acceptable salt thereof, a method for producing them, and a preparation containing them.

[0002]

2. Description of the Related Art Corticosteroids (also called corticoids) secreted from the adrenal cortex have a steroid skeleton and are roughly classified into mineral corticoids and glucocorticoids according to the difference in their physiological activities.

Of these, mineralocorticoids are hormones having a mineral-metabolizing action, are involved in the metabolism of inorganic salts, moderately suppress the excretion of sodium chloride and water, and are retained in the interstitium of tissues to cause renal failure. It has an action of promoting excretion of potassium and phosphoric acid, and is an essential substance for the life support of animals. Aldosterone, desoxycorticosterone, corticosterone, etc. are known as mineralocorticoids.

On the other hand, glucocorticoid is a corticoid having a glucose metabolism action. That is, glucocorticoids have the effect of metabolizing proteins in the body to carbohydrates, increase the storage of glycogen deposited in the liver, and the resistance of the animal body to shock, cold, trauma, poisoning, etc., that is, antiallergic action. It has the effect of exerting. Furthermore, the glucocorticoid also has an anti-inflammatory effect. As glucocorticoids, cortisone, hydrocortisone, prezonisolone, methylprezonisolone, triamcinolone, dexamethasone, parameterzone, clocortron, fluocinolone, clomethasone,
Betamethasone is known.

[0005] As described above, since the corticosteroid has various physiological activities, it is used as a therapeutic agent for stress, shock, allergic diseases and inflammatory diseases, but it is extremely insoluble in water. There is a drawback that. As water-soluble salts of these adrenocortical hormones, phosphoric acid esters, metasulfobenzoic acid esters and the like have been conventionally known.

[0006]

Under these circumstances, the present inventors have earnestly studied for a novel compound having an adrenocortical hormone action which is excellent in water solubility and also has a strong antioxidant action. Advanced. As a result, they have succeeded in synthesizing a compound in which ascorbic acid and an adrenocortical hormone are bound via phosphoric acid and a pharmacologically acceptable salt thereof, and have found that these compounds satisfy the above-mentioned object. The present invention has been completed by further studies based on these new findings.

[0007]

That is, the present invention is
(1) The following formula

[Chemical 2] [In the formula, R represents a hydrogen atom, a hydroxyl group, a methyl group or a methylene group. However, when it has a hydroxyl group at the 17-position of the skeleton of the steroid, it also includes its acylated product, and when R is a hydroxyl group, its ketone compound is also included. ] And a pharmacologically acceptable salt thereof (hereinafter,
This compound is called. ), (2) a method for producing them, and (3) a preparation containing them.

The present compound, whether it is a free compound or a pharmacologically acceptable salt thereof, can be appropriately used for the purpose of the present invention. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and other salts are also pharmacologically acceptable. Any salt can be used as appropriate.

As the corticosteroid used in the present invention, those having an alcoholic hydroxyl group at the 21st position of the steroid skeleton or those having a halogen atom at the 21st position of the steroid skeleton are used. Any one may be used. For example, mineralocorticoids such as aldosterone, desoxycorticosterone, corticosterone and cortisone, hydrocortisone, prezonisolone, methylprezonisolone, triamcinolone, triamcinolone acetonide, dexamethasone, parameterazone, clocortolone, clomethasone, betamethasone, etc. The glucocorticoid is exemplified.

This compound can be appropriately synthesized by the following two methods or in accordance with these methods. That is, (1) as represented by the following reaction formula, a corticosteroid (II) having an alcoholic hydroxyl group at the 21st position of the steroid skeleton and ascorbic acid-2-phosphate ester (III), The compound (I) is obtained by condensation in the presence of a dehydration condensation agent,

[Chemical 3] (2) Alternatively, as represented by the following reaction formula, a corticosteroid (IV) having a halogen atom at the 21st position of the steroid skeleton and ascorbic acid-2-phosphate (III) are deoxidized. Compound (I) of the present invention can be obtained by reacting in the presence of an agent.

[Chemical 4] Hereinafter, these two manufacturing methods will be described in more detail.

As a first method for obtaining the present compound, a corticosteroid (II) having an alcoholic hydroxyl group at the 21-position of the steroid skeleton and ascorbic acid-2-phosphate (III) are dehydrated and condensed. Examples include a method of condensation in the presence of an agent, for example, in pyridine. The ascorbic acid-2-phosphate ester (III) used in this reaction may be synthesized according to a method known as ascorbic acid-2-phosphate, or a commercially available one may be used. In addition, ascorbic acid is L type, but D
It may be L-shaped. When this is used for this reaction, for example, magnesium ascorbyl phosphate is passed through a sulfonic acid-based ion exchange resin to remove magnesium, and used in the form of a free acid. In addition, various dehydration-condensation agents can be used, but by using N, N′-dicyclohexylcarbodiimide (DCC), the condensation reaction proceeds sufficiently. The solvent used in this reaction is preferably pyridine or the like, but any solvent may be used as long as it does not inhibit this reaction. This reaction is completed at room temperature in about 1 to 5 hours.

As a second method for obtaining the present compound, a corticosteroid (IV) having a halogen atom at the 21st position of the steroid skeleton and ascorbic acid-2-phosphate (III) obtained by the above method are used. In a ketone in the presence of an organic amine, heating under reflux for several hours can be mentioned. The corticosteroid (IV) having a halogen atom at the 21st position of the steroid skeleton used in this reaction is
It can be obtained by a known method, for example, as follows. That is, an adrenocortical steroid having an alcoholic hydroxyl group at the 21st position of the steroid skeleton is reacted with p-toluenesulfonyl chloride in dimethylformamide (DMF) to form a chlorate at the 21st position of the steroid skeleton, or Further, this chloro form can be treated with sodium iodide in acetone to obtain an iodine form. In this reaction, the chloro form can be used for the reaction, but the iodine form can be preferably used because it has higher reactivity. The solvent used in this reaction is preferably ketones such as acetone or methyl ethyl ketone, but any solvent that does not inhibit this reaction can be used. Also,
As the deoxidizing agent, tertiary organic amines such as triethylamine and tributylamine are preferable. This reaction is completed by heating under reflux for about 1 to 5 hours.

The compound (I) of the present invention thus obtained may be obtained as a pharmacologically acceptable salt by a known method. For example, the desired compound is obtained by adding the obtained compound of the present invention in a suitable solvent to a substance that gives an alkali metal ion or an alkaline earth metal ion such as hydroxide, carbonate or hydrogen carbonate. be able to. The conversion into a salt may be performed after once isolating the compound of the present invention from the reaction solution, or may be performed without isolation from the reaction solution.

The present compound (I) thus obtained
Is a novel compound which has not been published in the literature and has an antioxidant action, an anti-inflammatory action and an anti-allergic action and is a very useful compound. Since the present compound has various actions as described above, it is a compound useful not only as a medicine such as an antioxidant, an anti-inflammatory agent and an antiallergic agent but also as a cosmetic material.

The diseases which can be treated by the antioxidant action of the present compound include, for example, cataract and ischemic organ diseases.

Examples of anti-inflammatory diseases which can be treated by the preparation of the present invention include hemorrhoids, rheumatoid arthritis, rheumatoid arthritis, osteomyelopathy, osteoarthritis, lumbago, gout attack, acute otitis media, and cystitis. , Prostatitis, toothache, uveitis, sinusitis, etc.

Examples of allergic diseases which can be treated by the preparation of the present invention include bronchial asthma, hay fever, allergic rhinitis, dietary allergic gastritis, allergic diarrhea, ulcerative colitis, stomatitis, and periarteritis nodosa. , Occlusive arteritis, endocarditis, urticaria, eczema, contact dermatitis, frickten, sympathetic ophthalmitis, allergic conjunctivitis and allergic keratitis.

When the present compound is used as a cosmetic material, it should be appropriately mixed with a cream, lotion, lotion, etc. for the purpose of absorbing ultraviolet rays and skin, or stabilizing other cosmetic materials. it can.

The preparation of the present invention is appropriately used orally or parenterally for the prophylaxis and treatment of various diseases mentioned above. Examples of the form of the preparation include solid preparations such as tablets, granules, powders, capsules, ointments and suppositories,
Alternatively, it can be appropriately prepared by any known method in the form of any of liquid preparations such as eye drops, injections and syrups.
These formulations include commonly used excipients, binders, disintegrants, thickeners, dispersants, reabsorption promoters, buffers, surfactants, preservatives, isotonic agents, stabilizers and Various additives such as a pH adjuster may be used as appropriate. Also, when the compound of the present invention is incorporated into cosmetics, the components usually used in cosmetics can be added.

The pharmaceuticals and cosmetics of the present invention may contain one kind or two or more kinds of the present compounds in an appropriate combination depending on the purpose and need.

When the present compound is used as a pharmaceutical, the dose of the present compound varies depending on the type of the compound used, the type of target disease, the weight of the patient, the age and the indication symptoms and the administration method, and for example, injection. In case of drug, adult 1
About 0.1 mg to about 30 mg once a day, and in the case of an oral preparation, it is advisable to administer several times daily for adults to about 1 mg to about 100 mg. When used as an eye drop, it is advisable to instill a substance having a concentration of about 0.01 (w / v)% to 0.5 (w / v)% once a few times and several times a day.

When the present compound is to be used in cosmetics, it is usually about 0.0, although it varies depending on the kind of the compound, the kind of cosmetic to be mixed and the purpose of mixing.
01-5%, preferably about 0.01-2%.

The formulation of the present invention may appropriately contain other adrenocortical hormone agents, antioxidants, anti-allergic agents, anti-inflammatory agents and / or other types of medicinal components unless the object of the present invention is impaired. Good.

[0024]

EXAMPLES The present invention will be described in more detail with reference to Examples and Experimental Examples.

Example 1 21- (L-ascorbic acid
2-phosphoryl) dexamethasone sodium salt L-ascorbic acid-2-phosphate magnesium salt 3.0 g was dissolved in 30 ml of water, and this was added to an amberlite 1R-120B (H + type) column (diameter 2 cm x length 35 cm). The aqueous solution obtained by removing magnesium through a vacuum is concentrated under reduced pressure on a water bath at 40 ° C or lower to obtain a residual oily substance. To this, 40 ml of pyridine was added, and 2.0 g of dexamethasone was further added to dissolve it, and the mixture was stirred at room temperature with stirring for N, N'-dicyclohexylcarbodiimide (D
CC) (3.5 g) is added and the mixture is stirred for 3 hours. Next, the precipitated DC urea is filtered off and the solvent is distilled off. 70 ml of water on the residue
Is dissolved in the mixture, the mixture is neutralized with a 2N sodium hydroxide solution, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure to remove a small amount of dexamethasone mixed with ethyl acetate.
Precipitated white crystals are collected by filtration and recrystallized from water-ethanol to obtain 1.5 g of the desired compound having a melting point of 195 to 196 ° C (decomposition). The IR is shown in FIG. TLC silica gel Rf = 0.71 (n-butanol:
Acetic acid: water = 4: 1: 1) Elemental analysis As C ₂₈ H ₃₅ FO ₁₃ PNa.H ₂ O Theoretical value (%): C, 50.15; H, 5.56 Actual value (%): C, 50 .39; H, 5.88

Example 2 21- (L-ascorbic acid
(2-Phosphoryl ) hydrocortisone magnesium salt 3.0 g of L-ascorbic acid-2-phosphate magnesium salt was treated in the same manner as in Example 1 to remove the magnesium, and the aqueous solution was concentrated to give 50 m of acetone as a residual oil.
1, 2.0 g of 21-iodohydrocortisone and 6 ml of triethylamine are added, and the mixture is heated under reflux on a water bath for 5 hours. Next, the solvent is distilled off, and 80 ml of 0.2N hydrochloric acid is added to the residue and dissolved with stirring, and unreacted steroid is extracted and removed with ethyl acetate. The aqueous solution was concentrated to 40 ml, and this was added to Amberlite 1R-120B (H +
Type) column (diameter 2 cm × length 35 cm), neutralized with basic magnesium carbonate, and further concentrated. Ethanol is added to the residue and the precipitated magnesium ascorbyl phosphate is filtered off, and then the solvent is distilled off. The residue was dissolved in 20 ml of water, the active portion was collected and concentrated with a column of Sephadex G-10 (diameter 3 cm × length 50 cm, eluent is methanol: water = 1: 1), and the precipitated white crystals were collected by filtration. Recrystallization from a small amount of water, melting point 164-1
0.91 g of the target compound at 65 ° C. (decomposition) is obtained. That I
R is shown in FIG. TLC silica gel Rf = 0.64 (n-butanol:
Acetic acid: water = 4: 1: 1) Elemental analysis As C ₅₄ H ₇₂ O ₂₆ P ₂ Mg.2H ₂ O Theoretical value (%): C, 51.50; H, 6.08 Actual value (%): C , 51.21; H, 6.45.

[Example 3] 21- (L-ascorbic acid
-2-Phosphoryl) triamcinolone acetonidonatri
Umium salt L-ascorbic acid-2-phosphate magnesium salt (1.5 g), triamcinolone acetonide (1.0 g), pyridine (30 ml) and DCC (2.0 g) were treated in the same manner as in Example 1 to give a melting point of 215 to 216 ° C. 0.4 g of the target compound (white crystal) of (decomposition) is obtained. TLC silica gel Rf = 0.71 (n-butanol:
Acetic acid: water = 4: 1: 1) Elemental analysis As C ₃₀ H ₃₇ O ₁₄ FPNa · H ₂ O Theoretical value (%): C, 50.56; H, 5.52 Actual value (%): C, 50 .85; H, 5.87

[Example 4] Rat carrageenin pleurisy
Effect of the present compound The effect of the present compound on rat carrageenin pleurisy was tested.

[Test substance] 21- (L-ascorbic acid-2-phosphoryl) dexamethasone sodium salt (abbreviation: Dex-PC).

[Test Method] In this test, 6-week-old male S. D. Strain rats (weight 163-184 g) were used. The rat was anesthetized with ether and 0.1 ml of a 2% λ-carrageenin solution was injected into the thoracic cavity to induce pleurisy. λ-
Five hours after the administration of carrageenin, Pontamine Sky Blue (60 mg / 2 ml / kg) was intravenously injected, and 20 minutes after that, the rat was exsanguinated to death. The thoracic cavity was opened, the exudate was collected, and the amount of exudate and the pigment concentration of the exudate were measured. Further, the test substance was dissolved in a 2% λ-carrageenin solution to a concentration of 0.1% and administered into the thoracic cavity (0.1 mg / si).
te).

[Test Results] The results are shown in Table 1.

[0032]

[Table 1] Effect of this compound on rat carrageenin pleurisy Exudate amount Dye leakage amount n (ml) (μg / site) Control group 1.65 ± 0.45 68.4 ± 23.3 9 Dex-PC 1.13 ± 0.24 * 43.7 ± 13.2 * 8 Each value shows the average ± standard deviation. Significant difference from control group *; p <0.05.

As is clear from Table 1, 0.1 mg / s
The dose of ite was 31.5% for each intrapleural effusion.
It was significantly suppressed to 36.1%. From these, it was found that the present compound is useful as an anti-inflammatory agent.

[Formulation Example 1] Oral tablet Compound of Example 2 50 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg Using the above ingredients as ingredients for one tablet, tablets are molded by a conventional method. If necessary, sugar coating may be applied.

[Formulation Example 2] Eye drops Compound of Example 1 100 mg Boric acid 700 mg Borax 400 mg Sodium chloride 500 mg Methyl p-oxybenzoate 26 mg Butyl p-oxybenzoate 14 mg Sterilized purified water Mix by the method to make eye drops.

[Formulation Example 3] Injectable compound Compound of Example 1 10 mg Sodium chloride 900 mg Distilled water Total amount 100 ml The above components are mixed by a conventional method to give an injectable solution.

[Formulation Example 4] Ointment Compound of Example 3 100 mg Hydrophilic ointment Total amount 100 g The above components are mixed by a conventional method to give an ointment.

[0038]

The corticosteroid derivative of the present invention is
It is highly soluble in water and has anti-allergic, anti-inflammatory and anti-oxidant effects, so it should be used advantageously for the prevention and treatment of various allergic and inflammatory diseases as well as cataracts and various ischemic organ diseases. You can Further, the present compound is also useful as a UV absorbing component of cosmetics, a skin beautifying component and a stabilizing component of other cosmetic materials.

[Brief description of drawings]

1 shows an infrared absorption spectrum (IR) of the compound synthesized in Example 1. FIG.

FIG. 2 shows an infrared absorption spectrum (IR) of the compound synthesized in Example 2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/58 ABL C07J 75/00 9051-4C

Claims (9)

[Claims] 1. The following formula: [In the formula, R represents a hydrogen atom, a hydroxyl group, a methyl group or a methylene group. However, when it has a hydroxyl group at the 17-position of the skeleton of the steroid, it also includes its acylated product, and when R is a hydroxyl group, its ketone compound is also included. ] The corticosteroid derivative represented by these, or its pharmacologically acceptable salt. 2. The chemical name is 21- (L-ascorbic acid-
A corticosteroid derivative according to claim 1, which is 2-phosphoryl) dexamethasone, or a pharmaceutically acceptable salt thereof. 3. The chemical name is 21- (L-ascorbic acid-
A corticosteroid derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 2-phosphoryl) hydrocortisone. 4. The chemical name is 21- (L-ascorbic acid-
2-Phosphoryl) triamcinolone acetonide, The corticosteroid derivative according to claim 1, or a pharmaceutically acceptable salt thereof. 5. A corticosteroid having an alcoholic hydroxyl group at the 21st position of the steroid skeleton and ascorbic acid-
The method for producing a corticosteroid derivative or a pharmaceutically acceptable salt thereof according to claim 1, which comprises reacting with a 2-phosphate ester in the presence of a dehydration condensation agent. 6. The corticosteroid derivative according to claim 1, wherein the corticosteroid having a halogen atom at the 21st position of the steroid skeleton is reacted with ascorbic acid-2-phosphate ester in the presence of a base. Alternatively, a method for producing a pharmaceutically acceptable salt thereof. 7. An antioxidant comprising the corticosteroid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. An anti-inflammatory agent comprising the corticosteroid derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 9. An antiallergic agent comprising the corticosteroid derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.