KR800000555B1 - Process for preparation of terpenoid ester of steroid - Google Patents

Abstract

A retinoic acid ester of a steroid(I, X =H, halogen; Y = H, β-OH, O; A = H, α-Me α-azido, α-bromo, α-chloro, α-fluoro, α-fluouomethyl; B = H; W = H2, (H,α-OH); Q, Z = OH, retinoyloxy) of pregnance series having antiinflammatory activity were prepd. by reacting a steroid having a hydroxyl group on at least one of positions 16α-, 17α-and 21- with retinoic acid derivs. in the presence of dehydrating agent or esterificating agent.

Description

Method for preparing retinoic acid esters of steroids

The present invention relates to a process for the preparation of retinoic acid esters of novel steroids, which are Fregnan series steroids with valuable pharmacological properties.

According to the present invention, 16α-, 17-α and / or 21-retinoairs of steroids having an anti-inflammatory action of a Fregnan series having one or more hydroxyl groups at 16α-, 17α- and 21-positions are prepared.

The steroidal retinoate prepared by the present invention can be administered topically or intralesionally to suppress and treat rashes.

The steroidal retinoate may be 16α-, 21- or 17-α-21-diretinoate, but 16α- or 17α- or especially 21-monoretinoate is preferred.

Rethic acid is present in several isomers, the most stable and common isomer of all-trans-rethic acid (also known as all-trans-vitamin A acid) derived from vitamin A (retinol). The steroidal retinoate of the present invention is preferably derived from all-trans-retinoic acid. Steroidal retinoate derived from other retinoic acid isomeric forms such as 11-bis-rethioic acid, 9-cis-rethionic acid, 13-cisrethionic acid, 9,13-di-cis-rethionic acid and retro-rethion acid Also included.

As used herein and in the claims, the terms “retinoic acid” and “retinoate” refer to all forms of retinoic acid, especially various cis and trans forms and mixtures thereof, unless otherwise indicated.

The steroidal retinoate of the present invention is capable of hydrolyzing or hydrolyzing 3,20-diketo-4- to hydro-pregnane or its 3-ene ether or at least one of 17α- and 21-positions. Preference is given to 3-desoxy [3,2-c] pyrazole derivatives having derivatives.

When the retinoate is 16α-retinoate, the compound of formula (I) or 1-dehydro, 6-dehydro derivative thereof is represented.

In the above structural formula,

X is hydrogen or halogen having an atomic weight of 100 or less,

Y is (H, β-OH) or oxygen, and when X is halogen, it is (H, β-halogen),

A is hydrogen, α-methyl, α-azido, α-bromo, α-chloro, α-fluoro, β-fluoro or α-fluoromethyl,

When B is hydrogen or Y is (H, β-OH), B is also methyl, fluorine, chlorine or bromine

W is H ₂ , (H, lower alkyl), (H, α-Cl), (H, α-OH), (H, α-retinoyloxy), (H, α-OR ¹ ) (where R ¹ is an acyl group of a hydrocarbon carboxylic acid having up to 12 carbon atoms or is CHT. T is hydrogen, lower alkyl, fluorine or chlorine),

Q is hydroxy, retinoyloxy, ORC wherein R is an acyl group of a hydrocarbon carboxylic acid having up to 12 carbon atoms, or when W is hydrogen or (H, lower alkyl), Q is also hydrogen or chlorine, or Together represent 16α, 17α-lower alkylidenedioxy groups,

Z is also hydrogen, chlorine, fluorine or OR ² when R is a hydroxy or retinoyloxy or Q is a hydroxy or retinoyloxy group (R ² is an acyl group of a hydrocarbon carboxylic acid having up to 12 carbon atoms).

Or 3-desoxy [3,2-cpyrazole] derivative or 6-dehydro derivative thereof if B is hydrogen, or 6,6-difluoro derivative or 1-dehydro derivative thereof if A is hydrogen to be.

3-desoxy [3,2-c] pyrazole derivatives may contain lower alkyl, cycloalkyl, aralkyl, aryl and hydrocarbon carboxylic acyl groups. The lower alkyl group in the 2′-position substituent in the lower alkyl group and the 3-desoxy [3,2-c] pyrazole derivative at W may have up to 6 carbon atoms, and preferably has up to 4 carbon atoms. Examples include methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl and isobutyl and the like. Other substituents in the 2'-position in the 3-desoxy [3,2-c] pyrazole derivatives include cyclopentyl, cyclohexyl, β-hydroxyethyl, benzyl, phenethyl, phenyl and halogen (especially fluorine), trifluor Romethyl, methyl, methoxy or nitro and phenyl (especially in the p-position) groups substituted with 2-, 3- and 4-pyridyl groups and the like.

The acyl groups of the compounds of the invention defined as R, R ¹ and R ² optionally present at the positions of the above-mentioned structural formula (I) and 3-desoxy [3,2-c] pyrazole derivatives are saturated, unsaturated, straight or branched chains. Or derived from hydrocarbon carboxylic acids having up to 12 carbon atoms which are aliphatic or cyclic or cyclic-aliphatic or aromatic or araliphatic or alkyl-aromatic and may be substituted with alkoxy having 1 to 5 carbon atoms or halogen such as chlorine, fluorine or bromine.

Typical acyl groups of the steroidal retinoate of the present invention are formic acid, acetic acid, propionic acid, trimethylacetic acid, butyric acid, isobutyric acid, valeric acid, isovaline acid, caproic acid, caprylic acid, capric acid, undecyl acid and lauric acid, and the like. Such as alkanes, substituted alkanes such as phenoxy acetic acid, trifluoroacetic acid and β-chloropropionic acid, adamantane-1-carboxylic acid and adamantine-2-carboxylic acid, benzoic acid, toluic acid and p-chlorobenzoic acid, etc. They are derived from aromatic and substituted aromatic acids, such as alkanes such as phenyl acetic acid and phenylpropionic acid, unsaturated acids such as acrylic acid and sorbic acid, or dibasic acids such as succinic acid, tartaric acid and phthalic acid. Such acyl groups have up to 8 carbon atoms, preferably up to 5 carbon atoms. As such an acyl group, an alkano group or benzoyl group of up to 5 carbon atoms is particularly preferable.

Steroidal 21-retinoate, in particular steroidal 21-all-trans-retinoate, has the following structural formula and its 1-dehydro, 6-dehydro and 1,6-bis-dehydroderivatives are useful for treating and inhibiting acne. Particularly effective preferred steroidal retinoate group.

In the above structural formula

A is hydrogen, methyl or fluorine

X is hydrogen or fluorine

W is H ₂ or (H, α-methyl) or (H, β-methyl) or (H, α-OH).

In addition, the ester suitable for the acne treatment in the above formula (II) is when at least one of X and W is hydrogen. Compounds of this type include 21-ol-trans-retinoate (4-pregnan-11β, 17α, 21-triol-3,20-dione, 21-ol-trans-retinoate) and 6 of the compound. -Dehydro and 1,6-bis dehydro derivatives (wherein A and X are hydrogen and W is H ₂ in the formula above).

Useful forms of the structural formula (II) compounds include β-methasone 21-retinoate (9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3, 20-dione 21-all-trans-retinoate), β-methasone 17-n valerate 21-all-trans-retinoate and dexamethasone 21-retinoate (9α-fluoro-16α-methyl-1, 4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-ol-trans-retinoate) and 6-dehydro, 1 (2) -dihydro and 1 (2) of this compound ) -Dihydro 6-dehydro derivatives (wherein A is hydrogen, X is fluorine, W is (H, methyl) and triamcinolone 21-retinoate (9α-fluoro-1,4 in the formula (II) compound) Pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione 21-all-trans-retinoate) and 6-dehydro, 1 (2) -dihydro and 1 ( 2) -dihydro-6-dehydroderivative (wherein A is hydrogen, X is fluorine and W is (H, -OH) and 6α-fluorohydrocortisone 21-ol-trans-retinoate and 1-dehydro, 6-dehydro and 1,6-bis-dehydro derivatives of this compound (A in the formula (II) compound Fluorine, X is hydrogen, W is H ₂ ) and 6α-methyl-9α-fluoro-4-pregnene-11β, 17α, 21-triol-3,20-dione 21-ol-trans-retinoate 6-dehydro, 1-dehydro and 1,6-bis-dehydro derivatives of this compound (wherein A is methyl, X is fluorine and W is H ₂ in the formula (I) compound).

Particularly preferred compounds of formula II are hydrocortisone 21-all-trans-retinoate.

As another steroidal 21-retinoate of the present invention, 6α-fluoro-9α-chloro-16α-methyl-1,4-pregnadiene-11β, 21-dione-3,20-dione 21-ol -Trans-retinoate and 4-pregnene-11β, 21-diol-3,20-dione 21-ol-trans-retinoate and 17α-chloro-1,4-pregnadiene-11β, 21-diol- 17-desoxy compound of structural formula (I) compound such as 3,20-dione 21-all-trans-retinoate and 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21 -Triol-3,20-dione 17-n-butyrate 21-ol-trans-retinoate, 6α, 9α-difluoro-16α, 17α-isopropylidenedioxy-1,4-pregnadiene- 11β, 21-diol-3,20-dione 21-ol-trans-retinoate and 2′-phenyl-6,16α-dimethyl-9α-fluoro-11β, 17α, 21-trihydroxy-20-cato- 4,6 presence furnace to the Nadi [3,2-c] pyrazol-17-acetate 21-all-trans-c ₁₇ has the hydrolysis is available derivatives such as retinoic benzoate It includes 21-retinoic Eight of 17,21- diol.

In addition to the 21-retinoate as the compound in the present invention, there are also the following.

Triamcinolone 16-retinoate 21-acetate (9α-fluoro-1,4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione 16-all-trans-retinoate 21-acetate 16α-retinoate and 6-dehydro, 1 (2) -dihydro and 1 (2) -dihydro-6-dehydro derivative thereof, triamcinolone 16,21-diretinoate (9α-fluoro- 16α, 21-diretinoate and 6 thereof, such as 1,4-pregnadiene-11β, 16α, 17α, 21-tet, 3,20-dione 16,21-di-ol-trans-retinoate) -Dehydro, 1 (2) -dihydro and 1 (2) -dihydro-6-dehydro derivatives, hydrocodone 17-all-trans-retinoate (4-pregnene-11β, 17α, 21-tri Retinoate of steroids of 17α-structural formula (I) compounds such as all-3,20-dione 17-all-trans-retinoate) and 1-dehydro, 6-dehydro and 1,6-bis-dehydro thereof Derivatives, Dexamethasone 17-Reti And β-methasone 17-retinoinoate (9α-fluoro-16α- and 16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-ol -Trans-retinoate), 9α, 11β-dichloro-21-fluoro-16α-methyl-1,4-pregnadiene-17α-ol-3,20-dione 17-ol-trans-retinoate, 2 ′ -Phenyl-6,16α-dimethyl-9α-fluoro-11β, 17α-dihydroxy-20-keto-4,6-pregnadieno [3,2-c] pyrazole 17-ol-trans -Retinoate and 9α, 21-difluoro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17-ol-trans-retinoate and the like, hydrocortisone 17, 21-Diretinoate (4-pregnene-11β, 17α, 21-triol-3,20-dione-17,21-di-ol-trans-retinoate), 9α-fluoro-16α-methyl-1 , 4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17,21-di-ol-trans-retinoate and 9α-fluoro-16β-methyl-1,4-preg Nadiene-17α, 21-diol-3,11,20-trione 17,21-di-ol 17α, 21-diretinoate of a structural formula (I) steroid such as trans-retinoate, or an anti-inflammatory steroid that is not within the scope of the structural formula (I) compound but belongs to retinoate is 6,16-dimethyl- 1,4,6-15-pregnatetriene-11β, 17α, 21-triol-3,20-dione 21-all-trans-retinoate, 16β-methyl-1,4,8 (9)- Pregnaterienne-11β, 17α, 21-triol-3,20-dione 17-propionate 21-ol-trans-retinoate, 9α-fluoro-11β, 21-dihydroxy-3,20- Diketo-1,4-pregnadieno [17α, 16α-d] oxazoline 21-ol-trans-retinoate and 3- (β-chloro ethoxy) -6-formyl-9α-fluoro- 16α, 17α-isopropylidenedioxy-3,5-pregnadiene-11β, 21-diol-20-one 21-ol-trans-retinoate and the like.

Steroidal retinoates, which are compounds of the present invention, are typically crystalline solids and include alkanols (e.g. methanol and ethanol), ethers (e.g. diethyl ether and dioxane and tetrahydrofuran), chlorinated hydrocarbons (e.g. methylene chloride and Soluble in organic solvents such as chloroform) but insoluble in water. This steroidal retinoate is liable to be decomposed by light, oxygen, heat or the like because five conjugated double bonds are present in the retinoyl group. For this reason, it is advisable to store this compound in an inert gas such as argon or nitrogen in dark areas.

The steroidal retinoate of the present invention is produced from steroidal alcohols that are commercially available in the ester production of steroids. However, since retinoic acid is susceptible to decomposition in the presence of light, oxygen, heat or acid, all processes are preferably carried out in the dark with an inert gas (nitrogen) and at room temperature or below in the presence of a neutral or alkaline medium. Such esterification reactions can, however, be carried out above room temperature and / or in the presence of an acidic medium, but high yields of pure steroidal retinoate are obtained when reacting in the presence of neutral or alkaline medium at room temperature or below room temperature. Thus, according to the present invention, a steroid having an anti-inflammatory action of a pregnan type having at least one hydroxyl group at the 16α-, 17α-, and 21-positions is reacted with retinoic acid in the presence of a dehydrating or esterifying agent or a reactive reionic acid derivative. Reaction with to obtain a Fregnan steroidal 16α-, 17α- and / or 21-retinoate having at least one hydroxyl group at the 16α-, 17α- and 21-positions.

The esterification can be carried out in several steps as follows without causing hydrolysis of the retinoate ester or under conditions that do not result in the decomposition of somewhat unstable retinoyl.

(a) the esterified retinoyl group in the steroid nucleus is transferred from one hydroxy substituent to another

(b) the ester group is selectively hydrolyzed at the 21-position of 16α- or 17α-retinoate or at the 16α-position of 17α-retinoate

(c) ether or ester protecting groups are removed from 11β-hydroxy or 16α-hydroxy and / or 21-hydroxy groups;

(d) removing the 21-hydroxy group by sulfonation, replacing the sulfonate group with iodine and then reducing the iodine

(e) converting the 21-hydroxy group to 21-chlorine or 21-fluorine by sulfonation and replacing the sulfonate group with chlorine or fluorine;

(f) Acylate 16α-, 17α or 21-hydroxy groups.

The conditions of this esterification reaction largely depend on the reactivity of the hydroxy group present in the 16α-17α- or 21-position to be esterified, and 11β in the case of 17α-retinoate if there is a highly reactive hydroxy group in the steroid molecule. Protect the hydroxy group and, in the case of 16α-retinoate, the 21-hydroxy group.

16α- and 21-hydroxygroups can be easily esterified under mild conditions and that is why 16α- and 21-monoretinoate or 16α, 21-diretinoate are corresponding 16α- or 21-ol or 16α, 21 -Diol i) reacting carbodiimide, α-alkynylamine, alkoxy acetylene or boron trifluorolide with retinoic acid in the presence of an inert solvent as a dehydrating or esterifying agent, or ii) reactive retinoic acid derivatives, in particular retinoyl chloride It can be prepared easily by reacting with a base in the presence of a base, with N-retinoylimidazole in the presence of a base, or with a retinoate of dicarboxylic acid N-hydroxyimide.

Preferred dehydrating agents in the first stage of this reaction are carbodiimides, especially dicyclohexyl carbodiimides or 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-P, used in equimolar amounts with retinoic acid. Toluenesulfonate. Each equivalent of diimide and retinoic acid was added to the steroid in an inert organic solvent, the mixture was allowed to stand, and the sample was then chromatographed to confirm that the steroidal alcohol was almost converted to the retinoic esters. An additional molar amount of mid is added. This reaction takes considerable time (more than 2 days). This reaction is preferably carried out at room temperature and in the presence of inert gas (nitrogen, etc.) at dark. Inert organic solvents used are acetonitrile, or chlorinated hydrocarbons (eg methylene chloride) or ethers (eg dioxane or especially tetrahydrofuran). Steroidal retinoate is separated and purified using extraction, chromatography and the like.

Another dehydrating agent-esterifying agent is ethoxyacetylene in an inert organic solvent such as ethyl acetate, 1-phenyl-2-methyl alinino-acetylene in an inert organic solvent such as chloroform, or in an inert organic solvent such as diethyl ether. As a catalyst an effective amount of boron-tri fluoride etherate is used.

In the second stage of this reaction, nearly animal quantities of N-retinoylimidazole (prepared from rethic acid and N, N′-carbonylimidazole) are used as preferred reactive derivatives, with the exception of 16α, 21-diesters. Anger should use double the amount. This esterification reaction is carried out in the presence of a base such as sodium methoxide, sodium amide or imidazolyl sodium, and an inert solvent such as anhydrous ether (especially dialkyl ether such as diethyl ether), dioxane or most preferably tetrahydrofuran. . This esterification reaction is also carried out at room temperature in the dark in the presence of an inert gas (nitrogen, etc.). Completion of the reaction is determined by thin layer chromatography, which takes about 15-30 minutes. The steroidal retinoate thus produced can be separated and purified in good yields using conventional methods such as chromatography. When retinoyl chloride is used as the reactive derivative, the base is preferably an organic tertiary amine which acts as a solvent such as pyridine or triethylamine. N-hydroxyimide retinoates used as reactive derivatives of retinoic acid include N-hydroxy-phthalimide retinoate and N-hydroxy-succinimide retinoate, which are used to convert retinoic acid in the presence of carbodiimide. It can be prepared by reaction with N-hydroxy-phthalimide or N-hydroxy-succinimide.

The 16α-monoretinoate of 16α, 21-diol is optionally optionally reacted at the 21-position with a weak alkali such as sodium bicarbonate in a water-soluble inert organic solvent, followed by 16α, 21-diacylation with retinoic acid or a reactive derivative thereof. It can manufacture by decomposing. However, when only one hydroxy group of 16α, 21-diol is converted into a retinoyloxy group, it is preferable to protect the other and then release it.

Therefore, the steroid 16α, 21-diol can be reacted with 1 equivalent of trifluoroacetic anhydride to convert 21-hydroxy group to 21 trifluoro acetate to protect. The 16α-hydroxy group can also be converted to retinoyloxy as described above. Finally, the 21-hydroxy group can be liberated by selectively hydrolyzing 16α-retinoate 21-trifluoroacetate with sodium azide or sodium benzoate in a water-soluble organic solvent such as methanol.

In a pyridine at 0 ° C., 16α, 21-diol was acetylated with 1 equivalent of acetic anhydride to obtain 21-monoacetate, and a 16α-hydroxy group was introduced by introducing an unstable and alkali stable protecting group to the 16α-hydroxy group. Is best protected. The 21-acetate group is then hydrolyzed in methanol with a weak alkali, preferably sodium bicarbonate, the 21-hydroxy group is esterified with retinoic acid or a reactive derivative thereof, and the 16-position protecting group is hydrolyzed with dilute acid. Remove it.

Protective groups in the 16α-position include tri (lower) alkyl silylethers (particularly trimethyl-silylethyl or 2-tetrahydropyranyl ether groups). The tri (lower) alkylsilylether group is introduced by reacting 16α, 21-diol 21-monoacetate with the corresponding tri (lower) alkylsilyl chloride in pyridine while the 2-tetrahydro pyranyl ether group is 16α, 21-diol 21-mono acetate is introduced by reacting a catalytic amount of dihydropyran with a strong acid. In this case any 11β-hydroxy group is protected, but is hydrolyzed with dilute acid, preferably dilute hydrochloric acid in methanol, to regenerate with 16α-hydroxy group upon removal of the protective ether group. 17-monoretinoate of 17α, 21-diol is monoesterized with a retinoic acid or a reactive derivative of retinoic acid in the presence of a dehydrating or esterifying agent at the 21-position and then the esterified retinoyl group is removed from the 21-hydroxy group. The conversion of 17α-hydroxy and treatment of the resulting 21-retinoate with a non-hydroxy base in anhydrous aprotic medium gives the best preparation by several processes to obtain 17-monoretinoate. The conditions of such reactions are described in US Pat. No. 3,891,631 and preferably non-hydroxy bases are the amide bases, phenolates or alcoholates of alkali metals, in particular alkali metal carbanionoid bases (e.g. lithium dimethyl cuprate). Lithium dibasic alkyl courates). As anhydrous aprotic medium, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or diethyl ether are preferred. The reaction is preferably performed at low temperature (approximately -40 ° C. is appropriate) and in the dark in the presence of an inert gas. Protonation proceeds with an aqueous ammonium salt such as ammonium chloride. The resulting 17α-retinoate is extracted, liberated and chromatographically purified using an organic solvent that is not mixed with water such as ethyl acetate.

17α-retinoate can be prepared directly by reacting 17α-ol with retinoic acid or a reactive derivative thereof under conditions sufficient to acylate the steric hindrance of 17α-hydroxy group. Thus, steroidal 17α-ol may be acylated in the presence of trifluoroacetic anhydride and strong acid catalyst (especially toluene-P-sulfonic acid) with retinoic acid or 4-dimethylamino pyridine and quaternary with retinoyl chloride. It can be acylated in the presence of amines (especially pyridine). Under conditions sufficient to acylate 17α-hydroxy groups, 11β-, 16α and / or 21-hydroxy groups may be acylated. Therefore, if such groups are present, these groups should be protected and if the 16α- or 21-hydroxy group is unprotected, 17α- unless the purpose is to prepare 16α, 17α- or 17α, 21-diretinoate. After acylation these groups should be removed.

When preparing the 21-monoretinoate of 16α, 21-diol, silyl ether or 2-tetrahydropyranyl ether group is preferable to protect the 16α-hydroxy group. It is also possible to use a nitrate ester group which can be introduced by the reaction of acetylnitrate with steroidal alcohol as a protecting group and can be removed by reduction with zinc and acetic acid. Another protecting group is the trifluoro acetyl group which can be introduced by esterification of steroids with trifluoro acetic anhydride in pyridine and can be removed by hydrolysis in weakly alkaline such as methanolic sodium bicarbonate solution.

Any 21-hydroxy group present in the starting steroid 17α-ol can be protected by the aforementioned groups. However, since the 17α-retinoate is easily prepared by moving the retinoyl group from the 21-position to the 17α-position in the 21-retinoate group, the method of directly acylating with retinoic acid or a reactive derivative thereof at the 17α-position is 21-. It is often used only for steroids that lack hydroxy groups. After introducing the esterified 17α-retinoyl group, the protective group is removed and the resulting 17α-retinoate is purified by chromatography-like method.

17α, 21-diasylate, wherein at least one acyl group is retinoyl, can be prepared by introducing two acyl groups in succession.

Thus, the first acyl group is introduced into the 21-hydroxy group and the second group is introduced into the 17α-hydroxy group (the 11β- and / or 16α-hydroxy group is protected), or the first acyl group is introduced into the 17α-hydroxy group. Move to hydroxy group. This latter method has the advantage that no protection group is required. This method can be used to introduce two retinoyl groups, or one to a retinoyl group and one to an acyl group. Such acyl groups are introduced under similar conditions as in the retinoyl group.

17α 21-diretinoate may be prepared by continuous acylation in 17α- and 21-hydroxy groups. In this case, the 11β- and 16α-hydroxy groups should be protected as described above. Directly acylate the 17α-retinoate 21-desoxy-17α-ol of 21-desoxy-17α-ol as above or 17α-acylate the corresponding 17α, 21-diol and then remove the 21-hydroxy group Or 21-acylated, which is prepared by converting to 21-fluorine or chlorine atoms, and then converting the retinoyl group from 21-hydroxy group to 17α-hydroxy group. The 21-hydroxy group is thus acylated in pyridine with sulfonylchloride, preferably methanesulfonyl chloride, and this group is converted to 21-sulfonate ester, preferably 21-methanesulfonate or 21-sulfo The 21-hydroxy group can be removed by reacting the nate in sodium iodide and acetic acid, preferably dimethylformamide to convert 21-sulfonate to 21-iodide and then removing the iodide. Alternatively acylated in pyridine with sulfonylchloride, preferably methanesulfonylchloride, to convert the 21-hydroxy group to 21-sulfonate ester, preferably 21-methanesulfonate and lithium chloride or lithium in dimethylformamide. The 21-hydroxy group can be converted to 21-fluorine or chlorine by reacting with fluoride to convert 21-sulfonate to 21-chloride or fluoride.

Retinoate esters, in particular 21-retinoate, 17α-retinoate 16α-retinoate, 16α, 21-diretinoate, and anti-inflammatory pregnane-based steroids 17, 21-diretinoate esters (anti-inflammatory activity seen in hydrocortisone Is a novel compound that has been shown to have acne-remedial effects in tests on hairless lino mice. Local treatment of the steroidal retinoate of the present invention (e.g., steroidal all-trans-retinoate, etc.) on the skin of rats of the scalp lesions reduces the hydration size of acne and almost irritates skin with retinoic acid. none. Preferred steroid retinoates include 3,20diketo-4-dehydropregnan or 3-enol or 3-desoxy [13,2-c]

When the pyrazole derivative is the retinoate and is 16α-retinoate, which is a compound of formula (I)-or (II), the compound is at least one hydroxyl group or hydrolyzable derivative in the 17α- and 21-positions. Has

It is surprising that the steroidal retinoate of the present invention has the effect of reducing acne without causing side effects such as inflammation on the skin. Because steroids with all-trans-retinoic acid and anti-inflammatory (effects of hydrocodone or prednisone) are equivalent amounts of the corresponding steroidal retinoate (e.g. hydrocortisone 21-all-trans-retinoate) When molar equivalents are used as acne lesions in lino mice (as in hairless lino mice), mixed steroids and all-trans-retinoate cause greater inflammation than inflammation caused by using only all-trans-retinoic acid. Because I knew the fact. In addition, the properties of mixed compounds that cause inflammation of the liver and acne treatment may be due to steroidal lower alkanoates (e.g. hydrocortisone 21-acetate) or steroidal esters (e.g. hydrocortisone 21) with similar lipophilic properties. No other steroidal esters, such as esters such as stearate). Moreover, retinoic acid of lipophilic nonsteroidal alcohols such as hydrocortisone 21-retinoate (eg 2-phenylethylretinoate) has no effect when used for the treatment of acne.

The excellent effect of the steroidal retinoate of the present invention on the treatment of acne was found in the experiments of hairless lino mice known as an effective experimental animal for screening acne specific drugs. In this experiment, a solution of steroidal retinoate (e.g. hydrocodone 21-all-trans-retinoate) of the present invention in an inert solvent such as acetone was prepared so that the concentration was 0.01% to 0.5%, typically 0.1%. The skin of rats was treated once a day for 6 days, the capillary area containing keratin (acne), the number of inflamed cells, and the thickness of the epidermis were measured before and after treatment, at which time the steroidal retinoate solution of the compound of the present invention. Site treated with, all-trans-retinoic acid solution, site treated with solvent only, site treated with free steroidal alcohol (e.g. hydrocortisone) and all-trans-retinoic acid together with steroidal alcohol The treatment site was compared The test results showed that the steroidal retinoate of the present invention did not cause inflammation when compared to the site treated with solvent only. It was found that the amount of capillary area and keratin was significantly reduced, but retinoic acid decreased the capillary area by treatment alone or in combination with steroidal alcohol but increased the number of inflamed cells in the treated skin. When treated only, the maternal area increased slightly.

Preferred compounds of the present invention have the effect of reducing acne without causing inflammation, which is a side effect caused by the solution of retinoic acid, and treating 0.02% of all-trans-retinoic acid solution for the same period when treated with 0.1% for 6 days. Hydrocodison 21ol-trans-retinoate, which exhibits the same effect as obtained.

Therefore, the present invention provides a cosmetic composition that can be used in the treatment of acne containing at least one steroid retinoate of the present invention as an active ingredient and containing a nontoxic carrier for cosmetic use. Such a composition can be mixed with a toxic carrier, steroidal retinoate, of the present invention into a form suitable for burns.

Furthermore, the present invention provides a method for treating acne by administering an effective amount of the compound of the present invention, steroidal retinoate, to a skin area infected with acne. The concentration of the composition containing steroidal retinoate (preferably steroidal all-trans-retanoate) is about 0.01% to 0.5%, preferably 0.025% to 0.1%, and is acne-infected skin with a non-toxic cosmetic carrier. It may be administered once or twice a day until local condition is good, but if acne is severe, it may be administered by injection. However, local administration of steroidal retinoate can be prevented from acne recurrence by continuing at least once every two days.

Such steroidal retinoate is dissolved in a liquid carrier, preferably a liquid carrier that can be mixed with water made of a hydrophilic liquid with high solubility, such as a solution of steroidal retinoate dissolved in ethyl alcohol and polyethylene glycol. . In general, steroidal retinoate is a steroidal retinoate of formula (I) as an active ingredient and mixed with conventional cosmetic diluents and carriers to form creams, lotions, solutions, gels, suspensions, aerosols and ointments. Preferred are steroidal all-trans-retinoate esters, particularly compositions containing said esters wherein at least one of X and W of formula (II) is hydrogen, and compositions containing hydrocortisone 21-all-trans-retinoate are particularly effective. Do.

The cosmetic composition of the present invention is prepared according to a conventional method.

The following examples illustrate the invention and do not limit the invention. The retinoic acid used as reagent in Examples 1 to 16 is an all-trans-retinoic acid from which a reionic acid ester is prepared. In Formulation Examples I and II, all-trans-retinoate esters are used. In the following examples, the all-trans-retinoic acid is in its isomeric form, i.e. 11-cis-retinoic acid, 9-cis-rethionic acid, 13-cis-rethionic acid, tetra-rethic acid or 9,13-di-cis- Substitution with retinoic acid yields the corresponding isomeric esters, namely 11-cis-retinoate, 9-cis-retinoate, 13-cis-retinoate, retro-retinoate or 9-13-di-cis-retinoate, respectively. .

Example 1

[9α-Fluoro-11oxygenated-16-methyl-1,4-pregnadiene-17α-, 21-diol-3,20-dione 21-retinoate]

+215°(클로로포름); 질량스펙트럼 M⁺=674; λmax메탄올 242nm(ε=20,000), 358nm(ε=33,000)A. (I) 350 mg (1 mmol) of anhydrous tetrahydrofuran 25 ml N-retinoylimidazole in the presence of nitrogen in the dark and 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, To a solution of 392 mg (1 mmol) of 21-triol-3,20-dione is added 28 mg (0.5 mmol) of sodium methoxide. Stir at room temperature for 15 minutes and evaporate the reaction in vacuo. The residue is chromatographed on a silica gel column, first eluted with petroleum ether, a mixture of petroleum ether and ether containing increasing amounts of ether, and finally with ether. Fractions were combined and evaporated as in thin layer chromatography to contain 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-retinoate Get the residue Purification by recrystallization with ether-petroleum ether. Yield: 230 mg, Melting point: 130 to 132 ° C;

+ 215 ° (chloroform); Mass spectrum M ⁺ = 674; λ max methanol 242 nm (ε = 20,000), 358 nm (ε = 33,000)

(II) In a similar manner, the following compounds are reacted with N-retinoylimidazole and sodium methoxide in tetrahydrofuran in the presence of nitrogen in the dark.

(1) 9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol 3,11,20-trione.

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione and

(3) 9α-fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione

The reaction products are separated and purified as described above, respectively, to obtain the following compounds.

(1) 9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 21-retinoate

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-retinoate and

(3) 9α-fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 21 retinoate

B. The compound of Example 1A (I) can be prepared as follows. In a suspension in which 392 mg (1 mmol) of 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione were dissolved in 50 ml of methylene chloride in the presence of nitrogen in the dark. 300 mg (1 mmol) of retinoic acid and 424 mg (1 mmol) of 1-cyclohexyl-3- (2-morpholinethyl) -carbodiimide meto-P-toluenesulfonate are added. After stirring for 17 hours at room temperature, retinoic acid and diimide are further added and stirred for 24 hours. The reaction mixture is subsequently extracted with 2% hydrochloric acid, water, 5% liquid sodium bicarbonate and water, then dehydrated with sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel G.F plate and developed with a mixed solvent of acetate and chloroform 1: 2.

G.F. The steroidal retinoate band was removed from the plate, extracted with ethyl acetate, filtered and evaporated under vacuum to obtain 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3 Obtain a residue containing, 20-dione 21-retinoate. Purification by recrystallization with ether-petroleum ether yielded 128 mg of a product having the same physical constant as the compound obtained in Example 1A (I).

Example 2

[11-Oxygenated-1,4-pregnadiene-17α, 21-diol-3,20-dione 21-retinoate]

A. 1-cyclohexyl- in a suspension of 360 mg (1 mmol) of 1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione in 50 ml of anhydrous acetonitrile in the presence of nitrogen in the dark 424 mg (1 mmol) of 3- (2-morpholinoethyl) -carbodiimidemetho-P-toluenesulfonate and 300 mg (1 mmol) retinoic acid are added. While stirring the reaction for 5 days, 1 mmol of retinoic acid and diimide are added every 1/3 period. The reaction mixture is poured into 2% hydrochloric acid, filtered and the precipitate obtained is dried. The dried precipitate was washed with a small amount of cold ethyl acetate and then silica gel G.F. Chromatography on a plate was developed with a solution of chloroform and ethyl acetate (1: 1). The steroidal retinoate band is stripped off and extracted with ethyl acetate. The extract is evaporated in vacuo to give a residue containing 1,4-pregnadiene-11β, 17α, 21-triol 3,20-dione 21-retinoate. Purification by recrystallization with ether gives 138 mg of product.

+252°(클로로포름); 질량스펙트럼 M⁺=642; λmax 메탄올 242nm(ε=19,600), 357nm(ε=32,000)Melting point: 216 to 218 ° C;

+ 252 ° (chloroform); Mass spectrum M ⁺ = 642; λmax methanol 242nm (ε = 19,600), 357nm (ε = 32,000)

B. In the same manner, 1,4-pregnadiene-17α, 21-diol-3,11,20-trione in acetonitrile in the presence of nitrogen in the dark was converted to rethion and 1-cyclohexyl-3- (2- Reaction with morpholinoethyl) -carbodiimidemetho-R-toluenesulfonate yields 1,4-pregnadiene 17α, 21-diol-3,11,20-trione 21-retinoate.

C. Alternatively, the 21-retinoate of this example was obtained by reacting the corresponding steroid 21-hydroxy compound with N-retinoylimidazole and sodium methoxide in tetrahydrofuran according to the method of Example 1A (I). Can be.

Example 3

[11-Oxygenated-4-pregnene-17α, 21-diol-3, 20-dione 21-retinoate]

A. (I) 300 mg (1 mmol) of retinoic acid and 1-cyclohexyl- in a solution of 362 mg (1 mmol) of 4-pregnene-11β, 17α, 21-triol-3 and 20-dione in 100 ml of methylene chloride. 424 mg (1 mmol) of 3- (2-morpholinolethyl) -carbodiimidemetho-P-toluenesulfonate are added. Stir for 15 hours in the dark in the presence of nitrogen at room temperature and then add four millimoles of retinoic acid and diimide at intervals of 24 hours. At this time, the measurement by thin layer chromatography shows that no starting steroid remains. The reaction mixture is filtered, evaporated under vacuum and chromatographed on silica gel G.F plate to develop with ethyl acetate and petroleum ether (1: 1) solution. After removing the steroidal retinoate band and extracting with ethyl acetate, the ethyl acetate extract was evaporated under vacuum to obtain a material containing 4-pregnene-11β, 17α, 21-triol-3,20-dione 21-retinoate. Get Purification by recrystallization from isopropyl ether and petroleum ether gave 276 mg of product.

+151.2°(클로로포름) 질량스펙트럼 M⁺=644, λmax 메탄올 242nm(ε=21,500), 357nm(ε=42,600)Melting point: 218-220 ° C,

+ 151.2 ° (Chloroform) Mass Spectrum M ⁺ = 644, λmax Methanol 242nm (ε = 21,500), 357nm (ε = 42,600)

(II) The compounds of this Example were prepared in the same manner as in Example 1A (I). N-retinoyl was converted to 4-pregnene-11β, 17α, 21-triol-3,20-dione in tetrahydrofuran in the presence of nitrogen. Obtained by reaction with imidazole and sodium methoxide.

B. 4-Pregnene-17α, 21-diol-3,11,20-triionolethionic acid and 1-cyclohexyl-3- (2-morphopoly) in methylene chloride in the dark in a similar manner as in Example 2A Noethyl) -carbodiimidemetho-P-toluenesulfonate.

Separation and purification in the same manner as above to obtain 4-pregnen-17α, 21-diol-3,11,20-trione 21-retinoate.

Example 4

[9α-fluoro-16-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-lower alkanoate 21-retinoate]

A. 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-valerate 21-retinoate

+175.1°(클로로포름); 질량스펙트럼 M⁺758; λmax메탄올 250nm(ε=24,900), 365nm(ε=29,400)(I) 9β-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-valerate in 250 ml of methylene chloride in the presence of nitrogen at room temperature To this solution was added 1.4 g of 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimidemetho-P-toluene sulfonate and 1 g of retinoic acid. The reaction mixture is stirred for 14 hours in the presence of dark and nitrogen, and 1.4 g of diimide and 1 g of retinoic acid are further added. After stirring for 24 hours in the dark, the reaction mixture is extracted with 5% dilute hydrochloric acid and water. The methylene chloride solution is dehydrated with magnesium sulfate and evaporated in vacuo and then developed on a silica gel GF plate with petroleum ether and ethyl acetate (2: 1) solution. The steroidal retinoate band is stripped off and extracted as ethyl acetate. Ethyl acetate extracts mixed under vacuum were evaporated to give 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-valerate 21-retinoate Obtain a substance containing Purification by recrystallization from isopropyl ether / hexane gave 1.1 g of pure 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-diol 17-valerate Obtain 21-retinoate. Melting Point 118-120 ℃

+ 175.1 ° (chloroform); Mass spectrum M ⁺ 758; λ max methanol 250 nm (ε = 24,900), 365 nm (ε = 29,400)

(II) 9α-fluoro-16α-methyl-1,4 pregnadiene-11β, 17α, 21-triol-3,20 in a dark, nitrogen-free manner at room temperature in a similar manner as in Example 4A (I) -Dione-17-valerate is reacted with retinoic acid and 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimidemetho-P-toluenesulfonate in methyleneloclide. The product was isolated and purified in the same manner as above to obtain 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-valerate 21-retino Get Eight

B. In the same manner as in Example 4A (I), the steroids described below in methylene chloride in the dark, under nitrogen pressure, were treated with retinoic acid and 1-cyclohexyl-3- (2-morphulinoethyl) -carbodiimidemetho. React with -P-toluenesulfonate.

(1) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-propionate

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-n-butyrate

(3) 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20 17-dionepropionate

(4) 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-n-butyrate

Each product was isolated and purified in a similar manner as in Example 4A to give the following compounds, respectively.

(1) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-propionate 21-retinoate

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-n-butyrate 21-retinoate

(3) 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-propionate 21-retinoate and

(4) 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-n-butyrate 21-retinoate.

Example 5

[11-Oxygenated-4-pregnene-17α, 21-diol-3,20-dione 17-retinoate and its 9α-fluoro-16-methyl-1-dehydro derivative thereof]

A. 4-pregnene-11β, 11α, 21-triol-3,20-dione 17-retinoate

A methyllithium solution in 0.3 ml (1.8 mol) of ether is added to a suspension of 100 mg of cuprous iodide in 1 ml of anhydrous tetrahydrofuran under nitrogen pressure at 0 ° C in the dark. After the mixture was stirred for 15 minutes, the temperature was lowered to −40 ° C., and 32 mg (0.05 mol) of 4-pregnene-11β, 17α, 21-triol-3,20-dione 21-retinoate was dissolved in 1 ml of anhydrous tetrahydrofuran. Add solution. The reaction mixture was stirred for 50 minutes in a dark at -40 ° C. under nitrogen pressure, poured into ammonium chloride solution, and shaken well. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed with water, dehydrated with magnesium sulfate and evaporated in vacuo to contain 4-pregnene-11β, 17α, 21-triol-3, -20-dione 17-retinoate. Get one substance. Purification by chromatography on silica gel GF plate was carried out with chloroform / ethyl acetate (3: 1). Removal of the maximal polar steroidal retinoate band and extraction with ethyl acetate yielded 22 mg of 4-pregnene-11β, 17α, 21-triol-3,20-dione 17-retinoate. Mass spectrum M ⁺ = 644

B. 4-pregnene-17α, 21-diol-3,11,20-trione 17-retinoate

In a similar manner to Example 5A, 4-pregnen-17α, 21-diol-3,11,20-trione 21-retinoate was reacted with cuprous iodide and methyllithium in anhydrous tetrahydrofuran to be isolated and purified. 4-pregene-17α, 21-diol-3,11,20-trione 17-retinoate is obtained.

C. 9α-fluoro-16-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate

A solution of methyllithium in 1.7 ml (1.8 mol) of ether was added to a suspension of 560 mg of cuprous iodide in 5.6 ml of anhydrous tetrahydrofuran at 0 ° C. under nitrogen pressure. The mixture was stirred for 15 minutes in the dark at 0 ° C. under nitrogen pressure, and the temperature was lowered to −40 ° C., followed by 9α-fluoro-16α-methyl-1,4-pregnadiene-11,17α in 5.6 ml of anhydrous tetrahydrofuran. A solution of 190 mg of 21-triol-3,20-dione 21-retinoate is added. The resulting mixture was stirred at -40 DEG C under nitrogen pressure for 20 minutes in the dark, poured into liquid ammonium chloride, shaken well, extracted with ethyl acetate, washed with water, dehydrated with magnesium sulfate and evaporated in vacuo to give 9α-fluoro-16α-. A residue containing methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate is obtained. It is developed by chloroform / ethyl acetate (3: 1) on a silica gel plate and purified by chromatography. The maximal steroidal retinoate band was removed, extracted with ethyl acetate, vacuum evaporated, and recrystallized with ether / petroleum ether to give 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 37 mg of 17α, 21-triol-3,20-dione 17-retinoate is obtained.

(II) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol- in dark at −40 ° C., under nitrogen pressure, in a similar manner as in Example 5C (I) 3,20-dione 21-retinoate is reacted with cuprous iodide and methyllithium solution. The product is isolated and purified to give 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate.

D. 9α-fluoro-16-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-triol 17-retinoate

9α-Fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20- in dark, at -40 ° C., under nitrogen pressure, in a similar manner as in Example 5C (I) Trion 21-Retinoate and 9α-Fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 21-retinoate React with methyl lithium in hydrofuran. Each product was isolated and purified in a similar manner to the above to obtain 9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17-retinoate and Obtain 9α-fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17-retinoate.

Example 6

[11-Oxygenated-4-pregnene-17α, 21-diol-3,20-dione-17,21-diretinoate and 11-oxygenated-16-methyl-9α-fluoro-1,4-pregnadi En-17α, 21-diol-3,20-dione-17,21-diretinoate]

A. 4-pregnene-11β, 17α, 21-triol-3,20-dione 17,21-diretinoate

Example 1A (I) In a similar manner to cows, under nitrogen pressure, 350 mg (1 mmol) of N-retinoylimidazole and 4-pregnen-11β, 17α, 21-triol-3,20-dione-17- 25 mg (0.5 mmol) of sodium methoxide are added to a solution of 644 mg (1 mmol) of retinoate in anhydrous tetrafluorofuran. After stirring for 15 minutes at room temperature, the mixture was evaporated in vacuo and chromatographed on a silica gel column, first eluting with petroleum ether, eluting with ether while increasing the amount of ether with petroleum ether and ether solution. The fractions are combined (as determined by thin layer chromatography) and evaporated to yield 550 mg of 4-pregnen-11β, 17α, 21-triol-3,20-dione-17,21-diretinoate-containing material. Purify by recrystallization from ether / petroleum ether.

B. 4-Frognen-17α, 21-diol-3,11,20-trione 17,21-diretinoate

Reaction of 4-pregnene-17α, 21-diol-3,11,20-trione 17-retinoate with N-retinoylimidazole and sodium methoxide under dark, nitrogen pressure in a manner similar to Example 6A . Isolation and purification give 4-pregene-17α, 21-diol-3,11,20-trione 17,21-diretinoate.

C. 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17,21-diretinoate

Cow, 175 mg (0.5 mmol) N-retinoylimidazole and 9α-fluoro-16α-methyl-1,4-prigadiene-11β, 17α, 21-triol- in 25 ml of mustetrahydrofuran under nitrogen pressure To a solution of 337 mg (0.5 mmol) of 3,20-dione 17-retinoate is added 14 mg (0.25 mmol) of sodium methoxide. After stirring for 15 minutes at room temperature, and evaporated in vacuo and chromatographed on a silica gel column, eluting with petroleum ether, eluting petroleum ether / ether with increasing ether amount, and finally eluting with ether. The fractions were combined and evaporated to yield 251 mg of 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17, Obtain a material containing 21-diretinoate. Purify by recrystallization from ether / petroleum ether.

D. In a similar manner as in Example 6C, the following compounds are reacted with N-retinoylimidazole and sodium tiltoxide in anhydrous tetrahydrofuran under dark, nitrogen pressure.

(1) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17-retinoate and

(3) Separation and purification of 9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17-retinoate product results in the following substances. Get

(1) 9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17,21-diretinoate

(2) 9α-fluoro-16β-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17,21-diretinoate and

(3) 9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione 17,21-diretinoate

Example 7

[16,21 diretinoate of 16-retinoate-21-acetate and 9α-fluoro-1,4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione]

Cow, 22.5 mg (0.05 mmol) of 9α-fluoro-1,4-pregnadiene-11β, 16α, 21-tetrol-3,20-dione 21-acetate in 2 ml of anhydrous tetrahydrofuran under nitrogen pressure and N Add 2.8 mg (0.05 mmol) of sodium methoxide to a solution of 17.5 mg (0.05 mmol) of retinoylimidazole. The mixture was stirred for 2 hours under dark and nitrogen pressure, the solvent was removed under vacuum, and the residue was chromatographed by developing with chloroform / ethyl acetate (3: 1) on a silica gel GF plate. The steroidal retinoate band was isolated, extracted with ethyl acetate and evaporated in vacuo to give 9α-fluoro-1,4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione 16-retino Obtain an acetate 21-acetate containing material. Purification by recrystallization with ether gives 17 mg (47%). M ⁺ 718; λ max methanol 237 nm (ε = 20,500), 357 (ε = 3,200)

B. 9α-Fluoro-1,4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione 16,21-diretinoate

9α-fluoro-1,4-pregnadiene-11β, 19α, 17α, 21-tetrol-3,20-dione in 5 ml of anhydrous tetrahydrofuran in the dark at room temperature and under nitrogen pressure in a similar manner to Example 7A 41 mg (0.1 mmol) and 70 mg (0.2 mmol) of N-retinoylimidazole are reacted with 5.6 mg (0.1 mmol) of sodium methoxide. After stirring for 2 hours at room temperature, dark and nitrogen pressure, the solvent was evaporated under vacuum and silica gel G.F. Chromatography on a plate was carried out with chloroform / ethyl acetate (3: 1).

The low polar steroidal diretinoate band is removed and extracted with ethyl acetate. The combined ethyl acetate extracts are evaporated in vacuo to give 9α-fluoro-1,4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione 16,21-diretinoate-containing material.

Example 8

[9α-Fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17-retinoate]

A. 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 11-trifluoroacetate

1 ml of trifluoroacetic anhydride was added to a solution of 1 mg of 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione in 5 ml of pyridine- Stir at 20 ° C. for 30 minutes, pour into dilute hydrochloric acid solution, filter, and dry. 9α-Fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20- A dion-trifluoroacetate containing material is obtained, which requires no further purification.

B. 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 11-trifluoroacetate-17-retinoate

Cow, 522 mg (1α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 11-trifluoroacetate in 20 ml of benzene under nitrogen pressure (1) Millimoles) and a solution of 0.6 ml of trifluoro acetic anhydride are cooled to 0 ° C., to which 300 mg (1 mmol) retinoic acid and 50 mg of P-toluenesulfonic acid are added. Stir until it is at room temperature and then stir for another 30 minutes at room temperature. Pour into water and extract with ether. The combined ether extracts were washed several times with liquid sodium bicarbonate, washed with water, dehydrated with magnesium sulfate and evaporated in vacuo to obtain 9α-fluoro-21-chloro-16α-methyl-1,4pregnadiene-11β, 17α- Diol-3,20-dione 11-trifluoro acetate 17 retinoate-containing material was silica gel GF Purify by chromatography on plate.

C. 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17-retinoate

9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-diol 11-trifluoroacetate 17-retinoate prepared in Example 8B was prepared. Dissolve in 25 ml of methanol, add 2.5 g of sodium benzoate, and stir for 30 minutes at room temperature and nitrogen pressure. After evaporation the product is treated with ether and water. The ether layer was washed with water, dehydrated with magnesium sulfate, the ether was evaporated in vacuo, and chromatographed by developing with ethyl acetate / chloroform (1: 2) on a silica gel G.F.plate. Remove the steroidal retinoate band, extract with ethyl acetate and evaporate in vacuo to give 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17 Obtain retinoate-containing substances.

Example 9

[Method for preparing 21-desoxy-17-retinoate from 21-hydroxy-17-retinoate]

A. 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate 21-methanesulfonate

674 mg (1 mmol) of 9α-fluoro-16α-methyl-1,4-prenadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate in 10 ml of pyridine under nitrogen pressure The dissolved solution is cooled to -20 ° C, 0.6 ml of re-distilled methanesulfonyl chloride is added, and left overnight at 20 ° C. The mixture is poured into dilute hydrochloric acid and filtered, and the precipitate obtained is washed with water and dried.

Purification by recrystallization with ether gives 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-retinoate 21-methanesulfonate.

B. 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17-retinoate

Cow, 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17,21 triol-3,20-dione 17-retinoate 21-methanesulfonate in 3 ml of dimethylformamide under nitrogen pressure 43 mg (1 mmol) of lithium chloride was added to a solution of 75.2 mg (0.1 mmol), and the mixture was stirred at 50 ° C. for 5 hours. Pour into water, extract with ether, wash the combined ether extracts with water, dehydrate with magnesium sulfate and evaporate in vacuo to give 9α-fluoro-21-chloro-16α-methyl-1,4-pregnadiene-11β, 17α-diol Obtain a -3,20-dione 17-retinoate-containing material.

C. 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-diol-3,20-dione 17-retinoate

Cow, 9α-fluoro-16α-methyl-1,4-pregnadiene-11, 17α, 21-triol-3,20-dione 17-retinoate 21-methanesulfo in 5 ml of dimethylformamide under nitrogen pressure To a solution of 300 mg of nate, 5 ml of acetic acid containing 300 mg of sodium iodide is added. Heat for 30 minutes in a water bath, cool and dilute with ether. Wash it with water, wash it with sodium bicarbonate solution and wash again with water. The ether solution was evaporated in vacuo and the silica gel G.F. Chromatography was developed with ethyl acetate / chloroform (1: 2) on a plate. The steroidal retinoate bands were isolated, extracted with ethyl acetate and vacuum evaporated to contain 9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α-diol-3,20-dione 17-retinoate Get the substance.

Example 10

[9α, 11β, 21-trihalo-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20-dione 17-retinoate]

A.9α, 21-dichloro-11β-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20-dione 17-retinoate

Dark, 428 mg (1 mmol) of 9α, 21-dichloro-11β-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20-dione in 10 ml of benzene at nitrogen pressure and The solution of 0.6 ml of trifluoroacetic anhydride was cooled to 0 ° C., and 300 mg (1 mmol) of retinoic acid and 50 mg of P-toluenesulfonic acid were added thereto. The mixture is stirred for 30 minutes and then left to stand at room temperature. The reaction mixture was poured into water, extracted with ether, washed several times with sodium bicarbonate solution and then with water. The ethereal layer was dehydrated with magnesium sulfate and evaporated in vacuo to give silica gel G.F. The plate was developed with ethyl acetate / chloroform (1: 2) and chromatographed. Remove steroidal retinoate band, extract with ethyl acetate and evaporate in vacuo to give 9α, 21-dichloro-11β-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20- Obtain dione 17-retinoate-containing material.

B.9α, 11β-dichloro-21-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20-dione 17-retinoate

Cow, 9α, 11β-dichloro-21-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3,20--dione 856 mg (2 mmol) in 10 ml of pyridine under nitrogen pressure To this solution, 1.272mg (4 mmol) of retinoyl chloride and 50mg of 4-dimethylamino-pyridine were added, and the mixture was stirred overnight at 50 ° C, in the dark and under nitrogen pressure. Water was poured into hydrochloric acid, extracted with ether, and the extract was extracted. Washed with water, dehydrated with magnesium sulfate and evaporated in vacuo, then chromatographed on silica gel column, eluting with petroleum ether, eluting with petroleum ether / ether solvent with increasing amount of ether and finally eluting with ether. The steroidal retinoate fractions determined by thin layer chromatography were combined and evaporated in vacuo to give 9α, 11β-dichloro-21-fluoro-16α-methyl-1,4-pregnadiene-17α-ol (ol) -3, 20-dione 17-retinoate-containing material is obtained.

Example 11

[Preparation of 9α, 11β-dihalo-21-desoxy-1,4-pregnadiene-17α-ol-3,20-dione 17-retinoate]

Using the method described in Example 10A, the following 9α, 11β-dihalo-21-desoxy-1,4-pregnadiene-17α-ol-3,20-diones were respectively retinoic acid, trifluoro Treatment in benzene with acetic anhydride and P-toluene sulfonic acid or in pyridine with retinoyl chloride and 4-dimethylaminopyridine using the method described in Example 10B.

The resulting compound is isolated and purified by the method described in Example 10A or Example 10B to obtain 17-retinoate esters compatible with the starting compounds described above, respectively.

Example 12

[Preparation of other 21-bisoxy-4-pregnene-11β, 17α-diol-3,20-dione 17-retinoate and its 1-dehydro 6-dehydro and 1,6-bis dehydro derivatives]

A. 21-Desoxy-4-pregnene-11β, 17α-diol-3,20-dione 11-trifluoro acetate

Similar to the method described in Example 8A, each of the following 21-desoxy-4-pregnene-11β, 17α-diol-3,20-dione is treated with trifluoroacetic anhydride in pyridine.

Each resulting compound is isolated and purified similarly to the method described in Example 8A to obtain 11-trifluoro acetate esters corresponding to the above-mentioned 11β-hydroxy starting compounds, respectively.

B. 21-Desoxy-4-pregnene-11β, 17α-diol-3,20-dione 11-trifluoroacetate 17-retinoate

Similar to the method described in Example 8B, the 49th 11-trifluoroacetate ester prepared in Example 12A was retinoic acid and P-toluene sulfone in the dark under nitrogen pressure at 0 ° C. in benzene and trifluoro acetic anhydride. Reaction with acid followed by separation and purification in a manner analogous to that described in Example 8B yields 11-trifluoroacetate 17-retinoate, which corresponds to 11β, 17α-dihydroxy starting compound described in Example 49 of Example 12A. Ester is obtained respectively.

C. 21-Desoxy-4-pregnene-11β, 17α-diol-3,20-dione-17-retinoate

In a manner similar to that described in Example 8C, each 11β-trifluoroacetate 17α-retinoate ester prepared in Example 12B is reacted in methanol of sodium benzoate at room temperature under nitrogen pressure.

The 17-retinoate ester corresponding to 4-pregnene-11β, 17α-diol-3,20-dione of the starting compound described in Example 12A, purified and purified according to the method described in Example 8B. Get each.

Example 13

Preparation of [21-retinoate, 17α-retinoate and 17,21-diretinoate of 4-pregene-3,20-dione and 1-dehydro, 6-dehydro, 1,6-bisdehydro derivatives ]

A. 4-pregnene-21-ol-3,20-dione 21-retinoate and its 1-dehydro, 6-dehydro and 1,6-bisdehydro derivatives

Similar to the method described in Example 1A (I), each of the following 4-pregnene-21-ol-3,20-diones was added to N-retinoylimidazole and sodium methoxide in the dark under nitrogen pressure in tetrahydrofuran. Reaction, separation and purification give 21-retinoate ester corresponding to 21-hydroxy steroid.

B. 4-pregnene-17α, 21-diol-3,20-dione 17-retinoate

Each 4-pregnene-17α, 21-diol-3,20-dione 21-retinoate prepared in Example 13A using the method described in Example 5A (eg, the starting compound 21-retinoate or 1- 186, 211-216, 219-222, 225-244, 248 and 255-266) were treated with cuprous iodide and methyllithium in anhydrous tetrahydrofuran to separate and purify the resulting material. 17-retinoate of 4-pregnene-17α, 21-diol-3,20-dione is obtained, corresponding to 216, 219-222, 225-244, 248 and 255-266.

C. 4-pregnene-17α, 21-diol-3,20-dione 17,21-diretinoate

Each 4-pregnene-17α, 21-diol-3,20-dione 17-retinoate prepared in Example 13B using the method described in Example 6A was N-retinoylimidazole in the dark in the presence of nitrogen. And sodium methoxide. Isolation and purification of the product yielded 17,21 of 4-pregene-17α, 21-diol-3,20-dione, corresponding to 1-186, 211-216, 219-222, 225-244, 248 and 255-266. Diretinoate is produced.

Example 14

[4-Pregnene-11β, 17α, 21-triol-3,10-dione 21-9,10-cis-retinoate and its 1-dehydro derivative thereof]

Example 1 A (I) using a method similar to 4-pregnene-11β, 17α, 21-triol-3,20-dione and 1,4-pregnadiene in the dark in the presence of nitrogen in anhydrous tetrahydrofuran -11β, 17α, 21-triol-3,20-dione are reacted with N- (9,10-cis-retinoyl) imidazole and sodium methoxide, respectively. The product was isolated and purified by the method described in Example 1A (I) to obtain 4-pregnene-11β, 17α, 21-triol-3,20-dione 21-9,10-cis-retinoate and 1,4 Pregnadiene-11β, 17α, 21-triol-3,20-dione 21-9,10-cis-retinoate is produced, respectively.

Example 15

[21-Desoxy-21-chloro-prednisolone 17-retinoate]

A. 21-Desoxy-21-chloro-prednisolone 11-nitrate

2 g of 21-desoxy-21-chloro-prednisolone are added to ice-cooled acetyl nitrate made of 21 ml of acetic acid, 16 ml of acetic anhydride and 4 ml of fuming nitric acid with stirring at 0 ° C. After 2 hours at 0 ° C. the solution is poured into ice water and the resulting pale yellow solid is filtered and purified by chromatography on activated magnesium silicate (Florisil).

B. 21-Desoxy-21-chloro-prednisolone 11-nitrate 17-retinoier

This compound is prepared by reacting retinoic acid, trifluoro acetic anhydride, and P-toluenesulfonic acid in benzene in the same manner as in Example 8B.

C. 21-Desoxy-21-chloro-prednisolone 17-retinoate

4 g of zinc powder was added to a solution of 0.5 g of 21-desoxy-21-chloro-prednisolone 11-nitrate 17-retinoate in 40 ml of glacial acetic acid, and stirred for 5 minutes at room temperature. Concentrate under reduced pressure and dilute a small amount with water. The title compound was extracted with ether, evaporated to dryness, and then silica gel G.F. Purify by chromatography on a plate.

Example 16

[Triamcinolone 17-Retinoate 21-Acetate]

A. Triamcinolone 21-acetate 11β, 16α-bis-trimethylsilyl ether

A solution of 1 g of triamcinolone 21-acetate in 4 ml of pyridine is reacted with 1 g of trimethylsilyl chloride (100% excess) at room temperature overnight. The reaction mixture is diluted with methylene chloride and washed with copper nitrate solution. Evaporation of the methylene chloride yields the desired 11β, 16α-diether, which can be used in the next section without further purification.

B. Triamcinolone 17-Retinoate 21- Acetate 11β, 16α-bis-trimethylsilyl ether

This compound is prepared by the method of Example 8B, by reacting the compound of claim A with retinoic acid, trifluoro acetic anhydride and P-toluene sulfonic acid in benzene.

C. Triamcinolone 17-Retinoate 21-acetate

0.5 ml of triamcinolone 17-retinoate 21-acetate-11β, 16α-bis-trimethylsilyl ether was added to 25 ml of methanol and 5 ml of 2N hydrochloric acid, and the mixture was left to stand for 1 hour. The solvent was removed in vacuo and the residue was treated with ether. do. The ethereal solution is washed with water, evaporated and dried. The product was subjected to silica gel G.F. Purify by chromatography on a plate, elute and recrystallize.

[Example 1]

[Composition for Topical Cosmetic Containing Steroidal Retinoate]

[A. Cream]

(1) hydrocortisone 21-hetinoate (0.1%)

(4-pregnene-11β, 17α, 21-triol-3,20-dione-21-retinoate

(2) dexamethasone 21-retinoate (0.25%)

(9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-retinoate

(3) betamethasone 17-valerate 21-retinoate (0.5%)

(9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 17-valerate 21-retinoate

[B. Ointment]

(1) hydrocortisone 21-retinoate (0.25%)

(2) hydrocortisone 21-retinoate (0.025%)

(3) betamethasone 21-retinoate (0.25%)

(9α-fluoro-16β-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-retinoate)

[C. Liquid]

(1) hydrocortisone 21-retinoate (0.1%)

(2) dexamethasone 21-retinoate (0.5%)

(3) prednisolone 21-retinoate (0.25%)

(1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione 21-retinoate)

[D. Lawson

(1) hydrocortisone 21-retinoate (0.1%)

[E. Gel]

(1) betamethasone 17-valerate 21-retinoate (0.25%)

(2) hydrocortisone 21-retinoate (0.025%)

Preparation Example II

[Composition for Injecting Internal Lesion of Steroidal Retinoate]

[A. Hydrocortisone 21-retinoate (0.1% -0.5%)]

(1) hydrocortisone 21-retinoate (aseptic precipitation)

(2) hydrocortisone 21-retinoate (aseptic precipitation)

[B. Prednisolone 21-retinoate (0.1% -0.5%)]

[C. Dexamethasone 21-retinoate (0.25% -0.5%)]

[D. Betamethasone 17-valerate 21-retinoate (0.25% -0.5%)]

Claims (1)

Pregnan-based anti-inflammatory steroids containing a hydroxy group in at least one of the 16α, 17α- and 21-positions are reacted with retinoic acid in the presence of a dehydrating or esterifying agent or by reacting with a reactive derivative of retinoic acid, A process for preparing 16α-, 17α- and or 21-retinoate of a Fregnan anti-inflammatory steroid having a hydroxy group in at least one of 17α- and 21-positions.