KR800000406B1 - Process for preparation of d-homosteroids - Google Patents

Abstract

D-homosteroids(I, R6 = H, F, Cl, Br, methyl; R11 = F, Cl, hydroxy; R9 = H, F, Cl, Br; R21 = residue group of sulfate or phosphate, aq. salt of carboxylic acid, acyloxy; R17a = hydroxy, acyloxy) useful as anti-inflammatory agent, were prepd. by reaction of D-homosteroid(II, R201 = hydroxymethyl, halomethyl) and sulfate or phosphate in the presence of acylating agent. Thus, 11β,17a-dihydroxy-21,21-diiodo-D-homopreg-4-ene-3,20-dione was dissolved in acetone, following by reaction with H2O K2HPO4 and o-phosphoric acid. The reaction product was rdfluxed in dark place to give I.

Description

Preparation method of D-homosteroid

The present invention relates to a method for preparing D-homosteroid of the following formula (I).

In the above structural formula

R ^{6 represents a} hydrogen, fluorine, chlorine, bromine or methyl group,

R ¹¹ represents fluorine or chlorine or a hydroxyl group.

R ⁹ represents hydrogen, fluorine, chlorine or bromine when R ¹¹ is a hydroxy group and chlorine or bromine when R ¹¹ is fluorine or chlorine

R ²¹ represents R when R ¹¹ is a hydroxyl group (R represents a sulfate or phosphate residue, or a dicarboxylic acid or tricarboxylic acid residue in water-soluble salt form), and when R ¹¹ represents fluorine or chlorine, acyloxy or R Indicate

R ^17a is a hydroxy group or an acyloxy group,

Dotted lines at 1,2-positions indicate any bond.

As used herein, the term halogen refers to fluorine, chlorine, bromine, iodine, and the acyloxy group can be derived from saturated or unsaturated aliphatic monocarboxylic acids, alicyclic or araliphatic or aromatic monocarboxylic acids containing up to 15 carbon atoms. . Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, keproic acid, enanthic acid, undecylenic acid, oleic acid, cyclopentyl propionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid, with particular preferred acyloxy groups having 1 to 4 carbon atoms. It is an alkanoyloxy group containing -7. The dicarboxylic acid or tricarboxylic acid residues may be derived from oxalic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, preferably succinic acid. desirable.

Structural formula (I) compounds in the text include D-homosteroids of the following structural formulas (I-1) and (I-2).

In the above structural formula

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or methyl group

R ⁹¹ represents hydrogen, fluorine, chlorine or bromine,

R ⁹² represents chlorine or bromine,

^L10 R is fluorine or chlorine,

R ²¹¹ represents R (R represents a sulfate or phosphate residue or a dicarboxylic acid or tricarboxylic acid residue in water-soluble salt form),

R ²¹³ represents an acyloxy group or R,

R ^17a represents a hydroxy or acyloxy group

Dotted lines at l, 2-position indicate any bond.

Among the 6-position substituted D-homosteroids represented by the above structural formulas, α-isomers are often used.

The D-homosteroid, which is a compound of formula (I), is prepared by the method of the present invention. That is, R ²⁰¹ of D-homosteroid of formula (II) is replaced with CH ₂ -R by reacting D-homosteroid of formula (II) with an acylating agent or sulfate or phosphate.

In the above structural formula

The dotted lines in R ⁶ , R ⁹ , R ¹¹ , R ^17a and 1,2-positions are as described above,

R ²⁰¹ represents a hydroxymethyl, halomethyl or diidomethyl group.

Acylation of the free hydroxy group at the 21-position of the D-homosteroid of formula (II) is a known method, preferably acyl chloride (e.g. acetyl chloride) or acid anhydride, in the presence of an acid binder such as pyridine. By treatment with an acylating agent such as, for example, succinic anhydride.

To selectively introduce an acyl group at the 21-position, the 21-halogen atom present in the D-homosteroid of formula (II) is replaced by an acyloxy group. For example, the D-homosteroid of formula II, wherein R ²⁰¹ is a halomethyl group, is heated with an appropriate alkali metal acylate or ammonium acylate in the presence of an acid corresponding to the acylate (for example potassium acetate in glacial acetic acid). Let's do it.

In particular, the 20-position diidomethyl group of the compound of formula II can be reacted with an acylating agent such as glacial acetic acid in the presence of a base such as diethylamine.

The method of introducing the phosphate or sulfate residues at the 21-position of the D-homosteroid of the formula (II) is similar to the acylation method of the 21-position described above, and the D-homosteroid of the formula (II) By reacting with sulfates (e.g. alkali metal hydrogen phosphates, alkali metal hydrogen sulphates or sulfur trioxide in pyridine)

Of the starting materials used in the reaction, the body does not describe the preparation method, which may be known or manufactured by a known method.

The above-mentioned D-homosteroid of formula (I) has an effect on the endocrine system and in particular has an anti-inflammatory effect. In addition, these compounds have a selective action, so the 9,11-dihalo-D-homosteroid has a weak phylogenetic effect but strong local action.

The D-homosteroid of formula (I) may be used in the form of a pharmaceutical formulation containing a suitable pharmaceutical carrier, which is an organic or inorganic inert carrier suitable for oral, dermal or subcutaneous administration. have. Water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, petroleum jelly and the like. Pharmaceutical formulations may be in solid form (tablets, dragees, medicinal preparations, capsules, etc.), semisolid forms (eg, ointments), or in liquid form (liquids, suspensions, emulsifiers, etc.). Alternatively, preservatives, stabilizers, wetting agents, emulsifiers, salts, etc. may be added to change the osmotic pressure or pH, and may also contain pharmaceutically effective substances other than the D-homosteroid of the present invention.

Generally, in the case of topical pharmaceutical preparations, the dosage range may be from about 0.01 to 1% and in the case of systemic therapy it may contain about 0.1 to 10 mg per dosage unit.

The pharmaceutical preparations may be prepared by mixing the D-homosteroid of formula (I) with known carriers of a nontoxic solid or liquid suitable for administration in a known manner and, if desired, in the form of the desired pharmaceutical dosage.

Next, examples of the present invention are illustrated.

Example 1

5 g of 11β, 17a-dihydroxy-21,21-diido-D-homopreg-4-ene-3,20-dione was dissolved in 50 ml of acetone and 0.5 ml of water, 5 g of K ₂ HPO ₄ and 85% ortho React with 0.3m1 phosphoric acid. The reaction mixture is quenched in the dark under reflux for 4 hours in a dark atmosphere, and a solution of 1.8 g of sodium bicarbonate dissolved in 25 ml of water is added, followed by evaporation of acetone. Acidified with diluted hydrochloric acid to obtain 3.1 g of D-homo hydrocortisone 21-phosphate as crystals. UV: ε ₂₄₂ = 14,800.

Starting materials are prepared by known methods of iodide at the 21-position of 11β, 17a-dihydroxy-D-homopreg-4-ene-ε, 20-dione by known methods.

Example 2

The method described in Example 1 was used with 80% sulfuric acid in place of KHSO ₄ orthophosphoric acid instead of K ₂ HPO ₄ to afford D-homohydro corisonone 21-sulfate. UV: ε ₂₄₂ = 14,200.

Example 3

Dissolve 10 ml of pyridine in 800 mg of 9-fluoro-11β, 17a-21-rihydroxy-D-homopregna-1,4-diene-3,20-dione, and the solution is room temperature with 390 mg of pyridine / 3 sulfur oxide complex. Stir at 16 h. The reaction product is then treated with 0.02 ml of water, stirred for 2 hours, and then the solution is added dropwise to 100 m of ether. The separated precipitate is suction filtered, washed with ether and dissolved in 15m1 of anhydrous methanol. 1N-sodium methylate solution was added to the solution to adjust the pH to 9.85, then left overnight and again to pH 9.85. The separated sodium sulfate was filtered by suction, the filtrate was concentrated, treated with ether, the fish precipitated was filtered by suction and dried in vacuo to give sodium (9-fluoro-11β, 17a-dihydroxy-D-homopregnna-1,4 608 mg of -diene-3, 20-dione-21-) sulfate are obtained. UV: epsilon 238 = 14,500. Starting materials are prepared as follows.

21-Acetoxy-17a-hydroxy-D-homo pregna-1,4,9 (11) -triene-3,20-dione is reacted with hypobromic acid and then dehydrogenated and debrominated 9 (11) 9-fluoro-11β, 17,21-trihydroxy-D-homoph having a melting point of 241 ° to 246 ° C by forming an epoxide and cleaving the epoxide group with hydrogen fluoride followed by saponification of 21-acetoxy group Obtain legna-1,4-diene-3,20-dione.

In a similar manner to the method described above, the following compounds are prepared:

21-acetoxy-9α, 11β-dichloro-17a-hydroxy-D-homopreg-4-ene-3,20-dione.

Melting Point: 225-228 ℃

UV: ε ₂₄₀ = 15,800

[α] _D = + 150 ° (C = 0.13% in dioxane)

21-acetoxy-9α, 11β-dichloro-17a-hydroxy-D-homopregnna-l, 4-diene-3,20-dione.

Melting Point: 222-224 ° C

UV: ε ₂₃₇ = 15,300.

[α] _D = + 142 ° (in C = 0.01% dioxane)

21-acetoxy-17a-hydroxy-9α-chloro-11β-fluoro-D-homopreg-4-ene-3,20-dione.

Melting Point: 238-239 ° C

UV: ε ₂₃₈ = 16,35O

[α] _D = + 131 ° (in C = 0.12% dioxane)

Melting Point: 266-268 ° C

UV: ε ₂₃₇ = 15,250

[α] _D = + 120 ° (in C = 0.14% dioxane)

UV: ε ₂₃₉ = 14,850

11β, 17a, 21-trihydroxy-D-homopreg-4-ene-3,20-dione 21-hemisuccinate

UV: ε ₂₄₂ = 15,900

21-acetoxy-6β, 9α-dichloro-11β-fluoro-17a-hydroxy-D-homopreg-4-ene-3,20-dione.

UV: ε ₂₃₆ = 14,500

21-acetoxy-6β, 9α-dichloro-11β-fluoro-17a-hydroxy-D-homopreg-4-2,30-dione.

UV: ε ₂₃₉ = 14,800

Claims (1)

By reacting the D-homosteroid of formula (II) with an acylating agent or sulfate or phosphate, R ²⁰¹ of D-homosteroid of formula (II) is replaced with CH ₂ -R ²¹ to D-homogene of formula (I) How to manufacture steroids.

In the above structural formula R ⁶ represents hydrogen, fluorine, chlorine or bromine or methyl group R ^l1 represents fluorine, driving chlorine or hydroxyl group R ⁹ represents hydrogen, fluorine, chlorine or bromine when R ¹¹ is a hydroxyl group, chlorine or bromine when R ¹¹ is fluorine or chlorine, R ²¹ represents R when R ¹¹ is a hydroxy group, where R represents a sulfate or phosphate residue or a dicarboxylic acid or tricarboxylic acid residue in the form of a water soluble salt. When R ¹¹ is fluorine or chlorine, it represents an acyloxy group or R R ^17a is a hydroxy or acyloxy group Dotted lines at 1,2-position indicate any bond R ²⁰¹ represents a hydroxymethyl, halomethyl or diidomethyl group.