JPH0533238B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel corticoid 21-thiazolidine carboxylic acid ester derivative and a method for producing the same. The corticoid 21-thiazolidine carboxylic acid ester derivative according to the present invention has stronger local anti-inflammatory action than systemic anti-inflammatory action, and is effective in treating acute and chronic eczema, seborrheic eczema, contact dermatitis, atopic dermatitis, and psoriasis. It is useful for the treatment of It is generally known that esterification of the 21st position of corticoids increases anti-inflammatory activity, but the corticoid 21-thiazolidine carboxylic acid ester derivative according to the present invention is a new compound and has extremely strong local anti-inflammatory activity. It is also characterized by extremely weak thymus atrophy, which is an indicator of systemic side effects. (Summary of the Invention) The gist of the present invention is the following general formula (I): (In the formula, B is

[Formula] is represented; Y represents a halogen atom; X is a hydrogen atom, and has 2 carbon atoms.
~10 alkoxycarbonyl groups or 2~ carbon atoms
4 represents an acyl group; R ¹ is α-position or β-position;
- represents an alkyl group having 1 to 5 carbon atoms; R ²
represents an acyl group having 2 to 5 carbon atoms. ) and a method for producing the same. (Structure of the Invention) To explain the present invention in detail, the corticoid 21-thiazolidinecarboxylic acid derivative of the present invention is represented by the following general formula (I). In the above formula, B is

Represents [formula]. Y represents a halogen atom selected from fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred. R ¹ represents an alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, and may be at either the α-position or the β-position, with α-methyl and β-methyl groups being particularly preferred. R ² represents an acyl group having 2 to 5 carbon atoms such as acetyl, propionyl, butyroyl. X represents a hydrogen atom; an alkoxycarbonyl group having 2 to 10 carbon atoms such as methoxycarbonyl, t-butoxycarbonyl, and benzyloxycarbonyl; or an acyl group having 2 to 4 carbon atoms such as acetyl, propionyl, butyroyl, etc.; A hydrogen atom is preferred. Specific examples of the corticoid 21-thiazolidine carboxylic acid ester derivatives according to the present invention include, for example, 9α-fluoro-11β-hydroxy-16β-
Methyl-17α-propionyloxy-21-(L-
4-thiazolidinecarbonyloxy)pregna-
1,4-diene-3,20-dione, 17α-butyryloxy-9α-fluoro-11β-hydroxy-
16β-methyl-21-(L-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,
20-dione, 9α-fluoro-11β-hydroxy-
16β-Methyl-21-(L-4-thiazolidinecarbonyloxy)-17α-valeryloxypregna-1,4-diene-3,20-dione, 9α-fluoro-11β-hydroxy-16α-methyl-17α- Propionyloxy-21-(L-4-thiazolidinecarbonyloxy)pregna-1,4-diene-
3,20-dione, 17α-butyryloxy-9α-chloro-11β-hydroxy-16β-methyl-21-(L
-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,20-dione, 21-(3-
Acetyl-L-4-thiazolidinecarbonyloxy)-17α-butyryloxy-9α-fluoro-11β
-Hydroxy-16β-methylpregna-1,4-
Diene-3,20-dione, 21-(3-t-butoxycarbonyl-L-4-thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β
-Methyl-17α-propionyloxypregna-
1,4-diene-3,20-dione, 21-(3-benzyloxycarbonyl-L-4-thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1 , 4-diene-3,20-dione,
17α-butyryloxy-9α-fluoro-11β-hydroxy-16β-methyl-21-(D-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,20-dione, etc., and 9α-fluoro- 11β-hydroxy-16β-methyl-17α-
Propionyloxy-21-(L-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,20-dione, 17α-butyryloxy-9α-
Fluoro-11β-hydroxy-16β-methyl-21
-(L-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,20-dione, 9α
-Fluoro-11β-hydroxy-16β-methyl-
21-(L-4-thiazolidinecarbonyloxy)-
17α-valeryloxypregna-1,4-diene-3,20-diene, 9α-fluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-21-(L-4-thiazolidinecarbonyloxy)
Pregna-1,4-diene-3,20-dione, etc.
L-thiazolidine carboxylic acid ester derivatives at position 21 are particularly preferred because they have high local anti-inflammatory activity. Next, the method for producing the compound of the present invention will be described.
X in general formula (I) will be explained in two cases. (A) When X is other than a hydrogen atom, that is, the following general formula (Ia): (In the formula, B, Y, R ¹ and R ² are as defined in the above general formula (I), and X ¹ has 2 to 2 carbon atoms.
10 alkoxycarbonyl groups or 2 to 4 carbon atoms
represents an acyl group. ) Corticoids indicated by
The 21-thiazolidine carboxylic acid ester derivative is
The following general formula (): (In the formula, B, Y, R ¹ and R ² are as defined in the above general formula (I).) A corticoid 21-hydroxy derivative represented by the following general formula (): (wherein, X ¹ is as defined in the above general formula (Ia), and Z represents a hydrogen atom or a halogen atom). In the above reaction, when Z in general formula () is a hydrogen atom, N,
N'-dicyclohexylcarbodiimide, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, 1-cyclohexyl-3-(4-
diethylaminocyclohexyl) carbodiimide, etc. are used. The amount used is corticoid 21−
The amount is 1 to 1.5 mol based on the hydroxy derivative (). As the solvent, aromatic amines such as pyridine are used, which may be diluted with halogenated hydrocarbons such as methylene chloride and dichloroethane. The reaction temperature is -10 to 40°C, and the reaction time is about 30 minutes to 20 hours. In addition, when Z in the general formula () is a halogen atom, aromatic amines such as pyridine or tertiary alkyl amines such as triethylamine are used as the base, and halogenated hydrocarbons such as chloroform and methylene chloride are used as the solvent. is used. The reaction temperature is -10℃ to room temperature, and the reaction time is
It takes about 10 minutes to 3 hours. (B) When X is a hydrogen atom, that is, the following general formula (Ib): (In the formula, B, Y, R ¹ and R ² are as defined in the above general formula (I).) The corticoid 21-thiazolidine carboxylic acid ester derivative represented by General formula (): (In the formula, X ² represents an N-protecting group.) After reacting with the N-protected thiazolidinecarboxylic acid in the presence of a coupling reagent, it is produced by removing the protecting group under acidic conditions. be done. Examples of the protecting group include t-butoxycarbonyl group, t-amyloxycarbonyl group, p-
Examples include biphenylisopropoxycarbonyl group, o-nitrophenylsulfenyl group, benzyloxycarbonyl group, trityl group, and p-methoxybenzyloxycarbonyl group. As coupling agents, N,N'-dicyclohexylcarbodiimide, 1-cyclohexyl-
3-(2-morpholinoethyl)carbodiimide,
Examples include 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodiimide and carbonyldiimidazole. The amount used is 1 mole of corticoid 21-hydroxy derivative.
~1.5 mol. Aromatic amines such as pyridine are used as solvents, and chloroform, methylene chloride,
It may be diluted with halogenated hydrocarbons such as dichloroethane. The coupling reaction is carried out at -10 to 40°C, and the reaction time is about 30 minutes to 20 hours. Removal of protecting groups can be carried out using ethyl acetate containing 5 to 20% hydrogen chloride, a mixed solution of 1N hydrochloric acid and acetic acid, 4N
The reaction is carried out in an acidic solvent such as a mixed solution of hydrochloric acid and dioxane, formic acid, trifluoroacetic acid, acetic acid containing hydrogen bromide, or hydrogen fluoride, and the reaction temperature is -20 to 30°C.
℃, and the reaction time is about 10 minutes to 5 hours. Corticoid 21− obtained by method (A) or (B)
Thiazolidine carboxylic acid ester derivative (I)
can be purified by recrystallization or the like. (Effects of the Invention) As described later, the corticoid 21-thiazolidine carboxylic acid ester derivative (I) of the present invention is extremely effective as an anti-inflammatory agent, especially a local anti-inflammatory agent, that has strong local anti-inflammatory action and weak systemic side effects. Useful. (Examples) Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples unless the gist thereof is exceeded. Example 1 21-(3-t-butoxycarbonyl-L-4-
thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1,4-diene-
3,20-dione 9α-fluoro-11β,21-dihydroxy-16β
-Methyl-17α-propionyloxypregna-
0.80 g of 1,4-diene-3,20-dione, 6 ml of pyridine, 3-t-butoxycarbonyl-L-4-
0.45 g of thiazolidinecarboxylic acid and 0.37 g of N,N'-dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 1.5 hours. After pyridine is distilled off under reduced pressure, methylene chloride is added to the residue to remove insoluble dicyclohexyl urea (DCU), and the mixture is washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated brine solution, and dried. The solvent was distilled off, and the residue was chromatographed using silica gel (benzene: ethyl acetate = 3:1).
21-(3-t-butoxycarbonyl-
L-4-thiazolidinecarbonyloxy)-9α-
Fluoro-11β-hydroxy-16β-methyl-17α
0.87 g of -propionyloxypregna-1,4-diene-3,20-dione was obtained as an amorphous solid. Example 2 9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxy-21-(L-4
-thiazolidinecarbonyloxy)pregna-
1,4-diene-3,20-dione 21-(3-t-butoxycarbonyl-L-4-thiazolidinecarbonyloxy) obtained in Example 1
-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1,4
-diene-3,20-dione 0.87g ethyl acetate
ml, 8 ml of 20w% hydrogen chloride/ethyl acetate was added under ice-cooling, and after 10 minutes, the temperature was returned to room temperature and stirred for 4 hours. The solvent is distilled off under reduced pressure from the reaction solution in which crystals have precipitated, to obtain white crystals, which are added to ice water containing sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, and dried. 0.66 g of crude crystals obtained by distilling off the solvent were recrystallized from ethyl acetate-n-hexane to give 9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxy-21-(L-4- Thiazolidine carbonyloxy)pregna-1,4-diene-
0.63 g of 3,20-dione was obtained. (Melting point: 140−145
℃) Example 3 17α-butyryloxy-9α-fluoro-11β-
Hydroxy-16β-methyl-21-(L-4-thiazolidinecarbonyloxy)pregna-1,
4-diene-3,20-dione 17α-butyryloxy-9α-fluoro-11β,
21-dihydroxy-16β-methylpregna-1,
Pyridine 6 to 0.8 g of 4-diene-3,20-dione
ml, 0.43 g of 3-t-butoxycarbonyl-L-4-thiazolidinecarboxylic acid and 0.36 g of N,N'-dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 6 hours. After adding methylene chloride to the reaction solution, insoluble materials are removed, and the organic layer is washed with a 10% aqueous citric acid solution, saturated sodium bicarbonate, and saturated brine, and then dried. The residue obtained by distilling off methylene chloride was purified by chromatography using silica gel (benzene:ethyl acetate = 4:1) to obtain 21-(3-t-butoxycarbonyl-L-4-thiazolidinecarbonyloxy). -17α-butyryloxy-9α-fluoro-
11β-hydroxy-16β-methylpregna-1,
0.61 g of 4-diene-3,20-dione was obtained as an amorphous solid. 21-(3-t-butoxycarbonyl-L-4-
thiazolidinecarbonyloxy)-17α-butyryloxy-9α-fluoro-11β-hydroxy-
16β-methylpregna-1,4-diene-3,20
- Dissolve 0.61 g of dione in 7 ml of ethyl acetate, add 20 w% - hydrogen chloride/7 ml of ethyl acetate under ice cooling, and add 10
After a few minutes, the mixture was returned to room temperature and stirred for 1.5 hours. Ethyl ether is added to the reaction solution in which crystals have precipitated, and after stirring, the crystals are collected and washed with ethyl ether. The crystals are added to a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried. The residue obtained by distilling off ethyl acetate was
Crystallization from n-hexane yields 17α-butyryloxy-9α-fluoro-11β-hydroxy-16β-methyl-21-(L-4-thiazolidinecarbonyloxy)pregna-1,4-diene-3,20-dione.
0.44g was obtained. (Melting point: 171-173°C) Example 4 21-(3-acetyl-L-4-thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1,4- Diene-3,20-dione 9α-fluoro-11β,21-dihydroxy-16β
-Methyl-17α-propionyloxypregna-
To 0.80 g of 1,4-diene-3,20-dione were added 6 ml of pyridine, 0.31 g of 3-acetyl-L-4-thiazolidinecarboxylic acid and 0.37 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into 2N hydrochloric acid and extracted with ethyl acetate. After removing insoluble dicyclohexyl urea, the mixture is washed with saturated sodium bicarbonate and saturated brine, and dried. The residue obtained by distilling off the solvent was subjected to chromatography using silica gel (benzene: ethyl acetate =
1:1) and further recrystallized with ethyl acetate-n-hexane to obtain 21-(3-acetyl-L-
4-thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1,4-diene-
0.75 g of 3,20-dione was obtained. (Melting point: 142-144°C) Example 5 9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxy-21-(D-4
-thiazolidine carbonyloxy)pregna-
1,4-diene-3,20-dione 9α-fluoro-11β,21-dihydroxy-16β
-Methyl-17α-propionyloxypregna-
0.70 g of 1,4-diene-3,20-dione, 6 ml of pyridine, 3-t-butoxycarbonyl-D-4-
0.39 g of thiazolidinecarboxylic acid and 0.32 g of N,N'-dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 4 hours. Pyridine was distilled off under reduced pressure, and methylene chloride was added to the residue to dissolve insoluble dicyclohexyl urea (DCU).
leave. The organic layer is washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine, and dried. The solvent was distilled off, and the residue was chromatographed using silica gel (benzene: ethyl acetate = 4:1).
21-(3-t-butoxycarbonyl-
D-4-thiazolidinecarbonyloxy)-9α-
Fluoro-11β-hydroxy-16β-methyl-17α
0.70 g of -propionyloxypregna-1,4-diene-3,20-dione was obtained as an amorphous solid. 21-(3-t-butoxycarbonyl-D-4-
thiazolidinecarbonyloxy)-9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxypregna-1,4-diene-3,20
0.70 g of -dione was dissolved in 10 ml of ethyl acetate, and 7 ml of 20w% hydrogen chloride/ethyl acetate was added under ice cooling, and after 10 minutes, the temperature was returned to room temperature and stirred for 3 hours. After the reaction, 50 ml of ethyl ether is added and stirred to precipitate white crystals, which are collected and washed with ethyl ether. The crystals are added to a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried. The crystals obtained by distilling off the solvent were recrystallized from ethyl acetate-n-hexane to give 9α-fluoro-11β-hydroxy-16β-methyl-17α-propionyloxy-21-(D-4-thiazolidinecarbonyloxy).
Pregna-1,4-diene-3,20-dione 0.37
I got g. Test Example (Method) In order to clarify the pharmacological effects of the compounds of the present invention, a local anti-inflammatory test and a thymus atrophy test, which is an indicator of systemic side effects, were conducted according to the following procedure. 1 Local anti-inflammatory test 10 male DDY mice weighing 15-20g were randomly administered.
Divide into groups of animals. Sodium chloride 0.9%, Tween 800.4 in distilled water
%, carboxymethyl cellulose 0.5%, and benzyl alcohol 0.9% are dissolved or suspended as a suspension solvent. The test compound is dissolved at a predetermined concentration in a mixture of suspension solvent: pyridine: diethyl ether = 1:4:5, and mixed with an equal amount of diethyl ether containing 10% croton oil to prepare a coating solution. Cut a commercially available 5 mm thick piece of felt into a 7 mm x 7 mm piece and attach it to a ring tweezers using instant adhesive. Dip this felt into the coating solution and apply it by rubbing it on the mouse's right ear with constant pressure without anesthesia. The left ear is left untreated. After 5 hours, the mice are sacrificed, and the left and right ears are cut and weighed. The rate of increase (%) in the weight of the right ear relative to the weight of the left ear is calculated as the edema rate.
The effect of the test compound is expressed as the percentage inhibition of edema in comparison with the values obtained in the control group. 2 Thymus atrophy effect test Male Wistar rats weighing 120 to 150 g were randomly divided into groups of 8 rats each. The test compound is dissolved in a solution of croton oil: cottonseed oil: ethanol = 1:89:10 at a predetermined concentration, and this is used as an injection solution. Rats were anesthetized by inhalation of ether, and 20 ml of air was injected into the subcutaneous tissue of the rat's back using a fine needle.
is injected to create an oval air sac. Immediately administer 0.5 ml of the above drug solution into the air pouch. After the rats wake up from anesthesia, they are allowed free access to food and water. Eight days later, the rats are exsanguinated to death, dissected, and the thymus gland removed and its wet weight measured. The effect of the test compound is expressed as the percentage of thymic atrophy compared to the values obtained in the control group. <Results> Both anti-inflammatory and thymic atrophy effects were determined using betamethasone 17,21-dipropionate as a standard substance and using the parallel line assay method.
The anti-inflammatory activity ratio and thymic atrophy activity ratio relative to dipropionate were calculated. The results are shown in Table 1 below. The compounds in the table are indicated by Example No. of the present application.

[Table] As is clear from Table 1 above, the compound of the present invention has a higher anti-inflammatory activity ratio than betamethasone 17,21-dipropionate, and a lower thymus atrophy activity ratio, which is an indicator of systemic side effects. Furthermore, the degree of separation (R) between anti-inflammatory activity and side effects is higher than that of betamethasone 17,21-dipropionate. As described above, the compounds of the present invention have strong local anti-inflammatory activity and weak systemic side effects, and are therefore useful as local anti-inflammatory agents.

Claims (1)

[Claims] 1 The following general formula (I): (In the above formula, B represents [Formula]; Y represents a halogen atom; X represents a hydrogen atom, an alkoxycarbonyl group having 2 to 10 carbon atoms, or an acyl group having 2 to 4 carbon atoms; R ¹ is represents an alkyl group having 1 to 5 carbon atoms at the α-position or β-position;
R ² represents an acyl group having 2 to 5 carbon atoms. ) Corticoid 21-thiazolidine carboxylic acid ester derivative. 2 The following general formula (): (In the above formula, B represents [Formula]; Y represents a halogen atom; R ¹ represents an alkyl group having 1 to 5 carbon atoms at the α-position or β-position;
R ² represents an acyl group having 2 to 5 carbon atoms. ) The corticoid 21-hydroxy derivative represented by the following general formula (): (In the above formula, X ¹ represents an alkoxycarbonyl group having 2 to 10 carbon atoms or an acyl group having 2 to 4 carbon atoms; Z represents a hydrogen atom or a halogen atom.) The following general formula (Ia) is characterized by reacting with: (In the formula, B, X ¹ , Y, R ¹ and R ² are as defined in the above general formulas () and ().)
A method for producing a corticoid 21-thiazolidine carboxylic acid ester derivative represented by 3 The following general formula (): (In the above formula, B represents [Formula]; Y represents a halogen atom; R ¹ represents an alkyl group having 1 to 5 carbon atoms at the α-position or β-position;
R ² represents an acyl group having 2 to 5 carbon atoms. ) The corticoid 21-hydroxy derivative represented by the following general formula (): (In the above formula, X ² represents an N-protecting group.) After reacting with the N-protected thiazolidinecarboxylic acid derivative represented by the formula, the following general method is characterized in that the protecting group is removed under acidic conditions. Formula: (1b): (In the above formula, B, Y, R ¹ and R ² are as defined in the above general formula ().) A method for producing a corticoid 21-thiazolidine carboxylic acid ester derivative.