JPH0368039B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to 21-alkoxysteroid compounds having excellent anti-inflammatory effects. Prior Art Regarding 21-alkoxy-17 ester derivatives of corticosteroids, there are few reports due to the difficulty in their production, and only the compound described in JP-A-60-4200 has been disclosed. Problems to be Solved by the Invention Various corticosteroids are commercially available as adrenocortical hormone agents for the prevention, treatment, and treatment of inflammatory skin diseases, asthmatic allergic diseases, rheumatic diseases, etc. for medical and general use. There is. However, corticosteroids commercially available for medical and general use do not yet have sufficient efficacy. It is an object of the present invention to provide steroid compounds that have a strong anti-inflammatory effect upon local administration. Means for Solving the Problems For the above purpose, the present inventors investigated in detail the reaction conditions for selectively etherifying the 21-position hydroxyl group, which had been considered difficult in the past, and achieved We succeeded in selectively etherifying hydroxyl groups. As a result, the inventors synthesized novel 21-alkoxysteroid compounds, discovered that they have particularly strong anti-inflammatory effects when administered locally, and completed the present invention. The present invention is based on the following formula (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a methylthiomethyl group, and R ² represents a carbon number 2
~7 alkanoyl groups are shown, and the wavy line indicates α or β coordination. ) represented by 21−
It is an alkoxysteroid compound. In the compound of the present invention of formula (), the number of carbon atoms is 1 to
The four alkyl groups include, for example, a methyl group, an ethyl group, and a propyl group. An alkanoyl group having 2 to 7 carbon atoms refers to an alkanoyl group having a linear or branched alkyl group, for example,
Examples include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and particularly preferred is an alkanoyl group having 2 to 4 carbon atoms. The compound of the present invention can be produced, for example, by the following method. A compound of formula () in which R ¹ is an alkyl group having 1 to 4 carbon atoms can be produced according to the following reaction formula (in the reaction formula, R ³ is an alkyl group represented by R ¹ , X is a halogen atom,
R ² has the same meaning as above. ). That is, first, in the presence of 1.0 to 1.5 equivalents of a base, a known compound of formula () is mixed with 1.0 to 10.0 of an alkyl halide represented by the formula R ³ -X (wherein R ³ and X have the same meanings as above). The compound of formula () is produced by reacting with 1.0 to 10.0 equivalents of dialkyl sulfate represented by the formula R ³ ₂ RO ₄ (wherein R ³ has the same meaning as above). In this reaction, bases include, for example, alkali hydrides such as sodium hydride and potassium hydride, alcoholates such as potassium tertiary butoxide, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali hydrides such as sodium carbonate and potassium carbonate. It is an alkali carbonate. The alkyl halide represented by the formula R ³ -X is, for example, methyl iodide, ethyl iodide, propyl iodide, etc., and is represented by the formula R ³ ₂ SO ₄
The dialkyl sulfate represented by is, for example, dimethyl sulfate. The reaction is carried out using ethereal solvents (e.g., tetrahydrofuran, dioxane, etc.),
Amide solvent (N,N-dimethylformamide,
dimethyl sulfoxide, hexamethylphosphortriamide, etc.) or a mixed solvent of the two.
This can be carried out by stirring at a temperature of 30 to 10°C for 1 to 10 hours. Next, the compound of formula () obtained above was added to 1 to 10 of trifluoroacetic anhydride.
A compound of formula () is prepared by reacting with an equivalent amount. This reaction can also be carried out in the presence of a base. Here, the base is, for example, an organic base such as pyridine, triethylamine, or diisopropylamine. The solvent is N,N-dimethylformamide, chloroform, dichloromethane, tetrahydrofuran, benzene, etc., or no solvent is used. The reaction temperature is -50 to 5°C, and the reaction time is 5 minutes to 3 hours. Next, the compound of the present invention can be obtained by acylating the 17-position hydroxyl group of the obtained compound of formula () and subsequently hydrolyzing the 11-position trifluoroacetate. The acylation is carried out without a solvent or in an organic solvent such as dichloromethane ^or benzene in the presence of an acid (e.g. para-toluenesulfonic acid, 60-70% perchloric _acid , etc.). ² has the same meaning as above.) A method of reacting with a carboxylic acid anhydride (for example, acetic anhydride, propionic anhydride, butyric anhydride, etc.), or without a solvent or in an organic solvent such as dichloromethane or benzene. trifluoroacetic anhydride,
In the presence of an alkyl chloroformate, etc., a carboxylic acid represented by R ² -OH (wherein R ² has the same meaning as above) (for example, acetic acid, propionic acid,
There is a method of reacting with butyric acid, etc.). These reactions are usually carried out at room temperature and are completed in 10 minutes to 5 days. Hydrolysis is performed by adding N, N,
This is carried out by adding an organic solvent such as N-dimethylformamide, tetrahydrofuran, or methanol, and an aqueous sodium acetate solution or an aqueous sodium bicarbonate solution, and stirring at 20 to 100°C for 10 minutes to 3 hours. On the other hand, the formula () where R ¹ is a methylthiomethyl group
The compound has the well-known following formula () It can be obtained by reacting a 21-hydroxysteroid compound represented by the formula (wherein R ² has the same meaning as above) with dimethyl sulfoxide in the presence of a carboxylic acid anhydride and a carboxylic acid. Here, the carboxylic acid anhydride is, for example, acetic anhydride, propionic anhydride, etc., and the carboxylic acid is, for example, acetic acid, propionic acid, etc. This reaction can be carried out without a solvent or in a nitrile solvent (eg, acetonitrile). The reaction temperature is room temperature to 100°C, and the reaction time is 10 minutes to 20 hours. The compounds obtained by each of the above reactions can be separated from the reaction mixture and purified by means known per se, for example, column chromatography, recrystallization, etc. Effects of the Invention The compound of formula () according to the present invention is a compound of closely related steroid compounds (for example, betamethasone 21-methoxide, betamethasone 17-valerate, and hydrocortisone 17-methylsuccinate described in JP-A-60-4200). It has an extremely superior local anti-inflammatory effect compared to 21-methoxide), and
Compounds of formula () in which R ² is an acetyl group, a propionyl group or a butyryl group are excellent. The compound of formula () according to the present invention can be used to treat various clinical skin diseases, such as acute eczema, chronic eczema, seborrheic eczema, atopic dermatitis, pediatric eczema, contact dermatitis,
It can be used to treat plaque psoriasis, etc. In addition, it can be used for the prevention, treatment, and treatment of other diseases accompanied by inflammation, such as asthma, allergic diseases, and rheumatic diseases. For this purpose, compounds of formula () can be administered topically in conventional dosage forms (eg ointments, creams, lotions, solutions, patches, etc.) prepared by conventional techniques. The usefulness of the compounds of the present invention will be shown below through test examples. Test Example 1 [Vasoconstriction test] The compound of formula () and comparative drugs (betamethasone 21-methoxide, betamethasone 17-valerate and hydrocortisone 17-methylsuccinate 21-methoxide) were each tested at 0.01% concentration in white petrolatum. (w/w) ointment. A fixed amount (approximately 20 mg) of this patch test bandage [Finchi Yambar; manufactured by Ebitest (Finland)] was applied to the flexor sides of both forearms of 20 healthy adult males. After 4 hours, the bandage was removed, and the remaining drug on the skin was gently wiped off with alcohol cotton, and 2 hours later,
The degree of pallor was determined after 4 hours. Judgment is based on the degree of pallor: ++ (significant), + (moderate), ± (mild),
−
Divided into four levels: (invalid), 3 points, 2 points,
A score of 1 or 0 was given, and the results of the 20 subjects were combined and calculated as an average value (maximum value 3.00). The results are shown in Table 1. The compound numbers in Table 1 have the same meanings as those described in Examples below.

【table】

[Table] Test Example 2 [Dilution vasoconstriction test] Betamethasone 17-propionate of the present invention
21-Methoxide and comparative drug betamethasone
17-valerate was prepared into ointments of various concentrations [0.005% and 0.00125% concentration (w/w)], each based on white petrolatum. This was tested in the same manner as Test Example 1, and the degree of pallor was measured after 2 hours and 4 hours. The results are shown in Table 2.

[Table] Examples Next, in Examples, the method for producing the compounds of the present invention will be explained in detail. Example 1 (1) Under nitrogen flow, 60% oily sodium hydride 1.23
After washing g with 20 ml of n-hexane, add 100 ml of tetrahydrofuran, and add 10 g of betamethasone under ice cooling.
Drop a mixed solution of 30 ml of g, N, N-dimethylformamide and 20 ml of tetrahydrofuran,
After the dropwise addition was completed, the mixture was stirred at the same temperature for 10 minutes. Next, 5 ml of methyl iodide was added and the mixture was further stirred for 5 hours. After the reaction, ice water was added, extracted with ethyl acetate, and the organic layer was diluted with saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with 5% hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. After that, the solvent was distilled off and the resulting crude product was washed with ethyl acetate to obtain 8.44 g of betamethasone 21-methoxide. This was recrystallized from a mixed solvent of ethyl acetate and methanol to obtain colorless prism crystals. mP228-230°C (2) A solution of 8.43 g of betamethasone 21-methoxide dissolved in 85 ml of pyridine was cooled to -25°C, 7.05 ml of trifluoroacetic anhydride was added dropwise, and after completion of the dropwise addition, the solution was stirred at the same temperature for 30 minutes. Ice water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed successively with 10% hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude crystals were recrystallized from a methanol-dichloromethane mixed solvent to obtain 6.66 g of betamethasone 11-trifluoroacetate 21-methoxide. mp216-219℃ (3) Add 1g of para-toluenesulfonic acid to a mixture of 4.10g of betamethasone 11-trifluoroacetate 21-methoxide obtained above, 15ml of propionic acid and 15ml of propionic anhydride, and stir at room temperature.
The mixture was stirred for several days. After the reaction was completed, 25 ml of N,N-dimethylformamide and 20 ml of 10% aqueous sodium acetate solution were sequentially added, and the mixture was stirred at about 60°C for 1 hour. Subsequently, water was added and extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane = 3:5) to obtain 2.60 g of betamethasone 17-propionate 21-methoxide (compound number 1). This was recrystallized from ethyl acetate to obtain colorless prism crystals. mP214-216°C Example 2 [Alternative method of Example 1 (2)] A solution of 84.30 g of betamethasone 21-methoxide obtained by the method of Example 1 (1) in 850 ml of N,N-dimethylformamide was cooled to -9°C. Then, 74 ml of trifluoroacetic anhydride was added dropwise over 30 minutes. -5℃ after dropping
The reaction solution was poured into water, the precipitate was filtered, washed with water, dried, and then washed with ethyl acetate.
97.9 g of 21-methoxide was obtained. Example 3 [Alternative method of Example 1 (3)] Under ice-cooling, 70.5 ml of propionic acid was added dropwise to 134 ml of trifluoroacetic anhydride, and after stirring at room temperature for 15 minutes, the procedure was carried out in Example 1 (2) or Example 2. Obtained betamethasone 11−
95.0 g of trifluoroacetate 21-methoxide was gradually added, and the mixture was further stirred for 4 hours. After the reaction is complete,
N,N-dimethylformamide 475ml, water under ice cooling
285 ml and 186 g of sodium acetate were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with saturated brine, saturated aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: acetone: chloroform: hexane = 1:
3:5) and recrystallized from 95% aqueous ethanol to obtain the same betamethasone as that obtained in Example 1(3).
45.3 g of 17-propionate 21-methoxide was obtained. Example 4 [Alternative method 2 of Example 1 (3)] Betamethasone 11-trifluoroacetate 21-methoxide obtained in Example 1 (2) or Example 2
To a solution of 2.0 g in 10 ml of dichloromethane, 2 ml of propionic anhydride and 0.1 ml of 70% perchloric acid were sequentially added.
Stirred at room temperature for 80 minutes. After the reaction, add N,
10 ml each of N-dimethylformamide and 10% aqueous sodium acetate solution were added, and the mixture was stirred at about 60°C for 1 hour. Subsequently, water was added and extracted with ethyl acetate.
The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from 95% aqueous ethanol to obtain the same betamethasone 17-propionate 21-methoxide as obtained in Example 1 (3).
1.33g was obtained. The following compound was obtained by the same method as in the above example. Betamethasone 17-acetate 21-methoxide (Compound No. 2) mp257-261℃ Betamethasone 17-Butyrate 21-Methoxide (Compound No. 3) mp150-151℃ Betamethasone 17-isobutyrate 21-methoxide (Compound No. 4) mp127-130℃ Betamethasone 17 -Valerate 21-methoxide (Compound No. 5) mp101-103℃ Betamethasone 17-isovalerate 21-methoxide (Compound No. 6) mp106-108℃ Betamethasone 17-acetate 21-ethoxide (Compound No. 7) mp250-252℃ (decomposition) Betamethasone 17-Propionate 21-Ethoxide (Compound No. 8) mp208-211℃ Betamethasone 17-Butyrate 21-Ethoxide (Compound No. 9) mp106-109℃ Betamethasone 17-Acetate 21-Propoxide (Compound No. 10) mp228-230℃ Betamethasone 17 -Propionate 21-Propoxide (Compound No. 11) mp203-205℃ Betamethasone 17-Butyrate 21-Propoxide (Compound No. 12) mp168-169℃ Dexamethasone 17-Acetate 21-Methoxide (Compound No. 13) mp242-245℃ Dexamethasone 17 -Propionate 21-methoxide (Compound No. 14) mp216-217℃ Dexamethasone 17-butyrate 21-methoxide (Compound No. 15) mp172-173℃ Dexamethasone 17-acetate 21-ethoxide (Compound No. 16) mp211-213℃ Dexamethasone 17-Pupionate 21-Ethoxide (Compound No. 17) mp194-195℃ Dexamethasone 17-butyrate 21-ethoxide (Compound No. 18) m.p189-190℃ Dexamethasone 17-propionate 21-propoxide (Compound No. 19) mp165-167℃ Example 5 1.00 g of betamethasone 17-propionate was dissolved in 50 ml of acetonitrile, 4.21 ml of acetic anhydride, 3.16 ml of dimethyl sulfide and 1.27 ml of acetic acid were added, and the mixture was heated under reflux for 4 hours. After distilling off the solvent, it was poured into a 10% aqueous sodium bicarbonate solution, the precipitate was collected, and subjected to silica gel column chromatography (developing solvent: acetone:chloroform:hexane = 3:3:16) to obtain betamethasone 17- 280 mg of propionate 21-methylthiomethylene oxide (compound number 20) was obtained. mp215~218℃

Claims (1)

[Claims] 1 formula (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a methylthiomethyl group, and R ² represents a carbon number 2
~7 alkanoyl groups are shown, and the wavy line indicates α or β coordination. ) represented by 21−
Alkoxy steroid compounds.