JPH0253794A - steroid compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to steroid compounds having excellent anti-inflammatory effects.

Several compounds have been previously reported in which the 17th or 21st position of a corticosteroid is substituted with a functional group, such as a functional group. For example, corticosteroid 21
As a derivative of a compound substituted in position,
Examples include compounds described in JP-A-6273, JP-A-5826-899, and JP-A-60-48999. In addition, as a compound in which the 17th position is completely substituted,
Examples include compounds described in Japanese Patent Publication No. 193900.

Problems to be Solved by the Invention However, their efficacy is still insufficient, and systemic side effects have become a problem in the fluticosteroid drugs that are commercially available for clinical and general use.

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 As a result of intensive study for the above purpose, the inventor has found Part 17
The present invention was completed based on the discovery that a steroid compound substituted with a specific functional group at the 21st and 21st positions has a strong anti-inflammatory effect when administered locally.

The present invention is based on the formula, Indicates an atom or a methyl group with α or β coordination, X represents a hydrogen atom or a halogen atom, n represents 1 or 2, and the dotted line between the 1 and 2 positions may be a double bond. It is a steroid compound represented by

In the present invention, the alkylthio group may be an alkylthio group having a linear alkyl group or an alkylthio group having a branched alkyl group. For example, the alkylthio group having 1 to 5 carbon atoms represented by R1 includes ethylthio group, ethylthio group, normal propylthio group, isopropylthio group, butylthio group,
Examples include isobutylthio group and pentylthio group, and the alkylthio group having 1 to 3 carbon atoms represented by R2 is methylthio group, ethylthio group, normal propylthio group, and isopropylthio group. Furthermore, halogen atoms include fluorine, chlorine, bromine, and the like.

The steroid compound represented by formula I of the present invention can be produced according to the following reaction formula (in the reaction formula, R'
The dotted line between R''
(X'' is a halogen atom, and R4 is an alkyl group forming an alkylthio group represented by R').

■ In other words, known methods (for example, U.S. Pat. No. 3,72
21 of formula H obtained by
The compound of the present invention (■) in which R2 is a halogen atom in formula I can be prepared by reacting -methanesulfonyloxysteroid with 10 to 30 equivalents of an alkali metal halide of formula (■). In this reaction, examples of the alkali metal halide include lithium chloride, lithium bromide, and sodium iodide. As the solvent, nitrile solvents (eg, acetonitrile, etc.), amide solvents (eg, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide, etc.), and mixed solvents thereof are used. Reaction time is 2 to 30 hours. In addition, the compound of formula π is combined with 10 to 30 equivalents of alkali metal iodide of formula V and 5O-
10 (1'C) for 2 to 30 hours, and then further reacted with 1.1 to 2 equivalents of ethyl mercaptan at room temperature for 5 to 30 minutes to prepare the compound (VI) of the present invention in which R1 is a hydrogen atom in formula I. In this reaction, the alkali metal iodide includes, for example, sodium iodide, potassium iodide, and lithium iodide.

As the solvent, nitrile solvents (eg, acetonitrile, etc.), amide solvents (eg, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide, etc.), and mixed solvents thereof are used.

The compound of formula ■ is converted into an alkali metal salt of thioacetate of formula ■ from 1°1 to
A compound of formula (1) can be prepared by reacting with 1.3 equivalents. In this reaction, the alkali metal thioacetate includes sodium thioacetate, potassium thioacetate, and the like. Examples of the solvent include a ketone solvent (for example, acetone, etc.)-alcohol solvent (for example, methanol, ethanol, etc.) mixed solvent, and an amide solvent (for example, N.

N-dimethylborumamide, dimethylsulfoxide, hexamethylphosphortriamide, etc.) are used. The reaction temperature is 50-80°C, and the reaction time is 1-5
It's time.

Next, by hydrolyzing the compound of formula (1) obtained above with a base, a compound of formula (2) can be produced. In this reaction, the base is, for example, hydrazine, sodium methoxide, etc., in an ether solvent (e.g., tetrahydrofuran, dioxane, etc.) or an alcoholic solvent (e.g., methanol, ethanol, etc.) at -20°C to 50°C. Allow to react for 5 to 30 minutes at a temperature of °C.

Next, the compound of formula (1) obtained above is reacted with 1.1 to 10 equivalents of alkyl halide in the presence of a base to produce the compound (X) of the present invention in which R3 is an alkylthio group in formula (2). Can be done. The base used in this reaction is, for example, an organic base such as tonoethylamine, diisopropylethylamine, or pyridine. The alkyl halide is an alkyl halide having an alkyl moiety of an alkylthio group represented by R8, and examples thereof include methyl iodite, ethyl iodite, and propyl bromide. As the solvent, nitrile solvents (eg, acetonitrile, etc.), halogen solvents (eg, dichloromethane, chloroform, etc.), amide solvents (eg, N,N-dimethylformamide, dimethylsulfoxide, etc.), and the like are usually used. The reaction temperature is -15~30℃, and the reaction time is 1
The duration is 5 minutes to 6 hours. The compounds obtained by each of the above reactions can be separated from the reaction mixture and purified by known means such as column chromatography, recrystallization, etc.

Effects of the Invention The compounds of the present invention have stronger local anti-inflammatory effects than conventionally known steroid compounds, and are clinically effective against various skin diseases,
For example, it can be used to treat acute eczema, chronic eczema, seborrheic eczema, atopic dermatitis, pediatric eczema, contact dermatitis, psoriasis vulgaris, and the like. 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, the compounds of the invention can be administered topically in conventional dosage forms prepared by conventional techniques, such as ointments, creams, lotions, solutions, patches, and the like. The carriers used are those already used in the manufacture of topical drugs, such as fats and vegetable oils of animal origin, saturated or unsaturated fatty acids,
Alcohols, such as polyhydric alcohols such as glycerin, propylene or polyethylene glycol, waxes, aliphatic hydrogen ash or water.

The compounds of the present invention may be present in the dosage forms described above.
It can be used in a dosage form containing 0.01% to 0.3% by weight, preferably in the range of 0.01 to 0.03% by weight.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples.

Example 1 0.70 g of hydrocortisone 17-methylthioacetate 21-mesylate was dissolved in a mixed solvent of 14 ml each of N,N-dimethylformamide and acetonitrile, 1.4 g of lithium chloride was added, and the mixture was heated under reflux for 4 hours.

After the reaction, the solvent was distilled off and the residue was treated with acetic acid. ”i
l' Extraction 15, the organic layer was washed with saturated sodium chloride, '4 <'-c, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 1
2) After separation and purification, the product was recrystallized from ethanol to obtain 0.35 g of 21-deoxyhydrocortisone 17-methylthioacetate 21-chloride.

m, p, 176-180℃ The following compound was obtained in the same manner as in Example 1.

21-deoxyhydrofrutidine 1-hoonitylthioacetate 21-chloride m, p, 160-162°C 21-deoxyhydrocortisone 17-itubrovir thioacetate 21-chloride m, p, 146-148°C 21-deoxyhydrofrutidine 1 fumedoxyacetate 21-chloride m, p, 179-181°C 21-deoxyhydrocortisone noa-methylthiopropionate 21-chloride m, p, 162-164°C 21-deoxyhydrocortisone 17-nitylthiobrobionate 21 -Chloride m, p, 133-134°C 21-deoxyhydrofrutidine 1-propylthioprobionate 21-chloride m, p, 151-
155°C 21-deoxybetamethasone 17-methylthioacetate 21-chloride m, p, 200-203°C 21-deoxybetamethasone 17-itubrovir thioacetate 21-chloride m,p, 207-210°C 21-deoxy betamethasone 17-methylthiopropionate 21-chloride m, I), 178-180°C 21-deoxybetamethasone 17-nitylthiopropionate 21-chloride mul, 152-154°C 21-deoxybetamethasone 17 - Itubrovir thiopropionate 21-chloride m, p, 168-1
71°C 21-deoxydexamethasone 17-methylthioacetate 21-chloride m, p, 196-198°C 21-deoxydexamethasone 17-methylthiopropionate 21-chloride m, p, 191-192°C 21-deoxydexamethasone 17-nitylthio Brobionate 21-chloride m, p, 162-164°C 21-deoxydexamethasone 17-itubrovir thiopropionate 21-chloride m, p, 90-95
°C Example 2 0.60 g of hydrocortisone 17-methylthioacetate 21-mesylate was dissolved in a mixed solvent of 7 ml each of N,N-dimethylformamide and acetonitrile,
0.50 g of sodium iodide was added, and after heating under reflux for 3 hours, 0.13 g of ethanethiol was added, and the mixture was stirred at room temperature for 20 minutes. After the reaction, the solvent was distilled off, and the remaining ethyl acetate extract was washed successively with a 10% aqueous sodium carbonate solution, 10% hydrochloric acid, and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 2: 3), and then recrystallized from ethyl acetate n-hexane. 21-deoxyhydrofrutidine 1-fumethylthioacetate 0.3
1 g was obtained.

+11. p, 202-203℃ The following compound was obtained by the same method as in Example 2.

21-Deoxyhydrocortisone 17-ethyl acetate m, p, 1.42--1.43''c.

2l--j Oxyhydroflutizone 17-itubropylthioacetate m, p, t 61-164°C 21-deoxyhydrocortisone 17-medoxyacetate m, p, 186-189°C 21-deoxyhydrocortisone 17-methylthiopro pionate m, p, 154-156°C 21-deoxyhydrocortisone 17-nitylthiobrobionate m, p, 112-114°C 21-deoxyhydrocortisone 17-itubrovir thiobrobionate m, p, 58-62°C 21-deoxybetamethasone 17-methylthioacetate m, p, 217-220°C 21-deoxybetamethasone 17-itubropyruti A
)゛Hide)・n+, p, 1.44-147°C 21-deoxybetamethasone 17-methylthiopropionate m, p, 212-213°C 21-deoxybetamethasone 17-nitylthiopropionate m, 185-189°C 21-deoxybetamethasone 17-itubrovir thiobrobionate m, p, 203-205°C 21-deoxydexamethasone 17-methylthioacetate m4), 164-166°C 21-deoxydexamethasone 17- Methylthiopropionate m, p, 100-103°C 21-Deoxydexamethasone 17-nitylthiobrobionate m, ri, 158-159°C 21-Deoxydexamethasone 1-propylthiobrobionate m, p, 175-177 °C Example 3 (1) Hydrocortisone 17-methylthioacetate 2
1.65 g of 1-mesylate was dissolved in a mixed solvent of 25 ml of acetone and 5 mQ of methanol, 1.07 g of potassium thiosulfate was added, and the mixture was heated under reflux for 2.5 hours. After the reaction, extraction with ethyl acetate, 10% aqueous sodium carbonate solution,
After washing successively with 5% hydrochloric acid and saturated brine, it was dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 3:5) to separate and purify it to obtain 21-deoxyhydrocortisone 17-methylthioacetate. 0.79 g of -1,21-thioacetate was obtained.

(2) 21-deoxyhydrocortisone 17-methylthioacetate 0.78 g of 21-thioacetate was dissolved in 15 ml of tetrahydrofuran, 0.2 ml of hydrazine hydrate was added under cooling with ice salt, and the mixture was stirred at the same temperature for 15 minutes. Ice water was added to the reaction solution, extracted with ethyl acetate, and 1
After washing successively with 0% hydrochloric acid and saturated brine, it was dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n hexane = 3:5) to separate and purify 21-deoxyhydrocortisone 17-methylthioacetate 21 -0.40 g of thiol was obtained.

(3) 21-deoxyhydrocortisone 17-methylthioacetate 0.39 g of 21-thiol was added to N,N
-Dissolved in 10 ml of dimethylformamide and cooled with water, 0.35 mQ of triethylamine and 0.16 ml of methyl iodide.
yrf was added one after another, and the mixture was stirred at the same temperature for 4.5 hours. After the reaction, ice water was added, and insoluble materials were collected by filtration and washed with water. The crude product was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 3:5), and then recrystallized from aqueous ethanol to obtain 21-deoxyhydrocortisone 17-methylacetate 21-methylsulfide. 0.30 g was obtained.

m, p, 76-79℃ By the same method as in Example 3, the following compound was obtained.

21-deoxybeta methazone 17-methylthioacetate 21-methylsulfide m,p, 112-115°C 21-deoxybetamenazone 17-methylthioacetate 21-ethylsulfide m,p, 134-136°C 21-deoxybetamethasone 17-itubropylthioacetate 21-methyl sulfide mp, 185-1
88°C Test Example Compound of the present invention and comparative drug (Betamethasone 17
- valerate) respectively based on white petrolatum
, prepared into an ointment with a concentration of 0.01% (w/w). This was randomly assigned to a fixed amount (approximately 2
01Tg) The finished product was applied to the flexors of both forearms of 20 healthy male adults, the bandage was removed after 4 hours, the drug remaining 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),
- (invalid), and scores of 3 points, 2 points, 1 point, and 0 points were given respectively, and the results of 20 subjects were combined and calculated as an average value (maximum value 3.00).

The results are shown in Table-1.

From the results shown in Table 1, it is clear that the compounds of the present invention exhibit a high vasoconstrictor effect.

Table 1 (Note) a: 21-deoxyhydrocortisone 17-methylthioacetate 21-chloride b = 21-deoxyhydrocortisone 17-medoxyacetate 21-chloride c: 21-deoxybetamethasone 1-fumethylthioacetate 21-chloride

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents an alkylthio group having 1 to 5 carbon atoms or a methoxy group, and R^2 represents a hydrogen atom, a halogen atom, a carbon number 1 ~3 alkylthio groups, R^3 represents a hydrogen atom or an α- or β-coordinated methyl group,
X represents a hydrogen atom or a halogen atom, n represents 1 or 2, and the dotted line between the 1st and 2nd positions may be a double bond. ) is a steroid compound represented by