KR820002025B1 - Preparing process for hydro cortison derivatives - Google Patents

Abstract

17α-butyryloxy-11β-hydroxy-21-propionyloxy-4-pregnene-3, 20-dione(I) was prepd. by reacting hydrocortisone 17-butyrate with propionic acid anhydride. Topical applications of a salve contg. I to human caused marked vasoconstriction. I was absorbed by rat skin to a greater extent than hydrocortison or hydrocortison-17 butyrate. I was also less tonic following S.C. administration to rats than was betamathasone 17-valerate or hydrocortison 17-butyrate.

Description

Method of preparing hydrocortisone derivatives

The present invention relates to a process for preparing 17α-butyryloxy-11β-hydroxy-21-propionyloxy-4-progene-3,20-dione (1), ie hydrocortisone 17-butyrate 21-propionate. It is about.

Recently, various types of corticosteroids have been used as anti-rheumatic, anti-inflammatory, anti-allergic and anti-shock agents. Moreover, these corticosteroids have been widely used internally and externally recently as a method of administration. Most of these compounds have a structure in which the corticosteroid is substituted by methyl, hydroxy, halogen (bromine, chlorine or fluorine), esterified hydroxy or acetonated hydroxy, or a derivative of the corticosteroid described above. Thus they are significantly altered forms from naturally occurring corticosteroids such as, for example, triamcinolone, fluoro sinolone acetide, verametazone, dexamethasone and derivatives thereof. Although these compounds are clinically effective, they tend to exhibit side effects such as penetrating action, and some clinicians have been interested in the side effects of halogen-introduced structures. Moreover, each of these known compounds has a structure that is significantly altered from the naturally occurring corticosteroid structure, and their metabolism and excretory mechanisms in vivo are complex. Thus, even if they are administered externally they are not always safe.

Based on the background of these known steroids, the present inventors have conducted various studies for the purpose of developing steroids having a structure similar to that of naturally occurring corticosteroids and exhibiting excellent anti-inflammatory action when applied locally. . As a result, the present invention discloses that 17α-Butylyloxy-11β-hydroxy-21-propionyloxy-4-progene-3,20-dione, ie hydrocortisone 17-butylate 21-propionate, is the other hydrocortis It has been found to have a much higher optical anti-inflammatory action than the John derivative and commercially available agents for external administration. Based on this finding, the present inventors completed the present invention.

An object of the present invention is to provide a novel steroid whose structure is almost similar to that of a naturally occurring corticosteroid, which has excellent anti-inflammatory action and low side effects upon external administration.

Compound (1) of the present invention can be synthesized according to various methods, preferably the following methods. Namely, when hydrocortisone is reacted with compound (2) of general formula CH ₃ CH ₂ CH ₂ C (OR) ₃ , the corresponding 17α, 21- (1'-alkoxy-1'-propylmethylene-dioxy) -11β- Hydroxy-4-pregene-3,20-dione (3) is obtained. In the above general formula, R represents lower alkyl having 1-5 carbon atoms.

The reaction of compound (3) with an acid such as hydroxyl or an inorganic acid such as hydrochloric acid gives hydrocortisone 17-butyrate (4). Acylating compound (4) in its 21-hydroxy affords compound (1) of the present invention. Generally acylation is carried out using acylating agents such as propionic anhydride or halides (bromine or chlorine) in a solvent such as chloroform, methylene chloride, tetrahydrofuran, toluene or benzene in the presence of a base such as pyridine or triethylamine according to conventional methods. Is performed. When acid anhydrides are used, acylation is usually complete in pyridine within 2-3 hours at room temperature. If acid halides are used, the acylation is preferably carried out with cooling at 0-10 ° C. for about 3-5 hours. After completion of the acylation, the reaction solution was poured into ice water and extracted with a solvent such as chloroform to obtain compound (1). Alternatively, the reaction solution can be concentrated directly under reduced pressure to afford compound (1). Purification of compound (1) obtained by each method can be carried out by recrystallization or column chromatography.

Compound (1) of the present invention has a high local anti-inflammatory action and can be used for the treatment of skin types such as acute or chronic eczema, seborrheic eczema, irritable dermatitis, infant eczema, contact dermatitis and vulgar psoriasis. For these purposes, Compound (1) is administered locally in conventional dosage forms such as ointments, creams, lotions, liquid coatings, warnings and powders prepared by conventional pharmaceutical methods. Compound (1) may be used in the range of 0.01-5.0% by weight, preferably 0.05-2.0% by weight in the conventional form described above.

Compound (1) has much better anti-inflammatory and transdermal absorption than other hydrocortisone diesters. It is believed that this excellent action is due to the distillation and bonding of the two esters at positions 17 and 21 of hydrocortisone. That is, although compound (1) has a structure similar to that of a naturally occurring steroid structure and does not contain a substituent such as halogen, compound (1) is another derivative containing such a substituent. Has better anti-inflammatory action.

[Vascular contraction nerve test]

, +, ± 및 -로 기록하였으며, 이것을 각각 3,2,1 및 0으로 채점하였다. 각각의 연고에 대한 30인의 지원자의 채점을 총합하였다. 각각의 시험화합물의 전체 및 평균채점을 표 1에 도시하였다. 여기에서 전체 채점은 각각의 연고의 총합 채점의 값이며, 평균 채점은 지원자의 수로 전체 채점을 나누므로서 얻었다.Ointments based on Pedrolatum containing 0.1% of the compounds described in Table 1, respectively, were prepared. These ointments were adapted to all of the healthy adult male volunteers and then removed 4 hours later. 4 hours after ointment removal, the degree of vasoconstriction of the adapted area was

, +, ± and-were recorded and scored as 3, 2, 1 and 0, respectively. The total scores of 30 applicants for each ointment were summed. The total and average scores of each test compound are shown in Table 1. Here, the total score is the value of the total score of each ointment, and the average score is obtained by dividing the overall score by the number of applicants.

TABLE 1

Transdermal absorption test

Transdermal absorption of Compound (1) was tested using normal skin of rats and compared to transdermal absorption of hydrocortisone and hydrocortisone 17-butyrate.

1.0 ml of an aqueous solution containing 5 µg of the test compound was injected into a short glass tube fixed to the abnormal skin (4 cm 2) of the shaved mouse. After a period of time the recovery of the test compound in the remaining aqueous solution was tested by high compactor liquid chromatography.

Percutaneous absorption (%) of the test compound was calculated as follows, and the results are shown in Table 2. Here the mean and its standard error are recorded for each set of tests.

TABLE 2

Subacute Toxicity Test

화합물(1)Subacute toxicity of Compound (1) was investigated against hydrocortisone 17-butyrate and betamethazone 17-valerate under the same experimental conditions when administered serially subcutaneously to Wistar species mice for 30 days . Test compounds were suspended in 5% gum arabic at appropriate concentrations. Doses of 0.08, 0.4, 2.0, 10 and 50 mg / kg for compound (1), 0.08, 0.4 and 2.0 mg / kg for hydrocortisone 17-butyrate and 0.08, 0.4 and 2.0 mg / kg for beta metazone, respectively To animals once daily. Animals used as controls received 5% gum arabic during the same period. It was fatal when 50 mg / kg of Compound (1) was administered to females and males. In all animals treated with the test compound with a gradual increase in dosage, changes such as a decrease in body weight, a decrease in the number of WBCs, an increase in total cholesterol and a decrease in thymus, adrenal, spleen and mesenteric lymph node weights were evident, Thymus, adrenal gland, spleen and mesenteric lymph gland were prominent when examined histologically. At the same dosing dose, the changes caused by betamethazone 17-valerate were more severe than those caused by other compounds. In the urine analysis, there was no change in the treatment roots compared to the control muscles. In the recovery test conducted 30 days after the end of drug administration, changes in organs were almost recovered. In conclusion, the subacute toxicity of steroids by subcutaneous administration was as follows. Beta metazone 17- valerate> hydrocortisone 17-butyrate

Compound (1)

Hereinafter, the present invention will be described in detail with reference to Examples.

EXAMPLE

1) A solution of hydrocortisone (5 g) in dimethylformamide (5 mL) containing ethyl orthobutyrate (5 mL) and p-toluene sulfonic acid (200 mg) was heated with stirring at 110 ° C. for 3 hours. Pyridine (3 ml) was added to the reaction mixture. After evaporation of the solvent the residue was purified by column chromatography on silica gel and recrystallized from acetone-n-hexane to give hydrocortisone 17,21-cycle ethyl orthobutyrate (3 g). Melting Point: 166-167 ℃

2) A solution of hydrocortisone 17,21-cycle ethyl orthobutyrate (2.5 g) in methanol (200 mL) containing a saturated aqueous solution (2.5 mL) was left overnight at room temperature. After completion of the reaction, the mixture was purified by column chromatography on silica gel using chloroform and then recrystallized from acetone-n-hexane to give hydrocortisone 17-butyrate (1.2 g). Melting Point: 208-210 ℃

3) To a solution of hydrocortisone 17-butyrate (1.0 g) in pyridine (5 mL) was added propionic anhydride (2 mL) at 0 ° C., and the mixture was left at room temperature overnight. The reaction mixture was poured into ice water (100 mL) and then extracted with chloroform. The chloroform solution was washed with dilute HCl and water and then dried over anhydrous sodium sulfate. Chloroform was evaporated and the residue was recrystallized from benzene-n-hexane to give colorless crystals (1 g). Melting point: 79-84 ° C. Furthermore, a solution of the crystals dissolved in ethanol was added dropwise to water with stirring, and the precipitate formed was filtered and dried in vacuo over phosphorus pentaoxide at room temperature, whereby hydrocortisone 17-butyrate 21-propionate was a colorless crystal powder. As obtained. Melting Point: 117-117.5 (Decompose at 265-268 ℃)

NMR: (at C ₅ D ₅ N); 1.00 (3H, s), 1.00-1.30 (6H, m), 1.43 (3H, s), 4.48 (1H, m), 4.74 (2H, dd, J = 18 Hz, 6 Hz), 5.65 (1H, s ).

Claims (1)

17α-butyryloxy-11,21-dihydroxy-4-pregnene-3,20-dione is reacted with acylating agent propionic anhydride or propionic acid halide to react with 17α-butyryloxy-11β-hydroxy-21-propy Process for preparing onyloxy-4-pregnene-3,20-dione.