CS208160B2 - Method of making the steroid 16 alpha,17-b cyclohexen-and tetrahydronaphtalene-21-carboxyl acids of the pregnan series - Google Patents

Abstract

Steroids having the formula <IMAGE> wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are = O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, <IMAGE> phenyl or cyano and in addition hydroxy, halogen carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or CHR9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl may be used as intermediates in preparing compounds having antiinflammatory activity. The invention extends to acetals of the 21-aldehydes.

Description

The invention relates to a process for the production of steroid [16a _; 17-b] cyclohexene- and titrahydronaphthalene-21-carboxylic acids of the pregnanoic series and their esters.

The above ^steroids: dy corresponding to the formula I,

and their esters are useful as anti-inflammatory agents for topical administration.

In the general formula I and throughout the following, the general symbols have the following meanings:

X is hydrogen or fluorine; and

R 2 and R 3 are each independently hydrogen, C 1 -C 4 alkyl, or taken together with the double bond to which they are attached to form a benzene ring.

Such esters are contemplated as alkyl esters of 1 to 10 carbon atoms in the alkyl moiety, acyl esters and aralkyl esters.

In accordance with the invention, the stiroids of formula (I) above may be prepared from the corresponding 21-hydroxy-A ¹⁶ -steroids of formula (II),

by first converting the 21-hydroxy group by oxidation to the 21-carboxy group, and then the cyclohexane or tetrahydranaphthalene group is not condensed at the 16.17 position.

21-hydroxy and ¹⁶ -steToidy formula

II, which are starting materials ₍ in this process, or the corresponding 21-acyloxystenoids are known in the art; 21-acyloxyisteiroids are readily converted from 208160 / i).

The 21-hydroxy-tert-o-oxides were prepared using conventional methods.

The steroid of the above-mentioned formula ( ¹ ) can be oxidized to the corresponding aldehyde (III),

using either oxygen (or air) and a catalyst such as copper (II) acetate. The reaction may be carried out in an alcoholic solvent.

When the oxidation reaction mentioned above is carried out in the presence of oxygen (for example by introducing air into the reaction mixture), the reaction generally generates, in addition to the steroid 21-aldehyde of formula III, also the steroid 21-acetal formed by reaction with an alcoholic. a solvent (R 1 -OH), i.e. a steroid of formula IV.

The oxidation reaction is generally completed in a relatively short time. ie in about 1 hour.

If the reaction described above is allowed to proceed for a longer period of time, for example for more than 24 hours, the major product of eisser-20-dihydroxy-2,1-carboxylic acids corresponding to formula V is formed.

If the oxidation reaction in the reaction mixture as cosolvent · · neichá and water when the reaction takes time, resulting in addition of the ester of 20-hydroxy-21-carboxylic acid of the above general · · V also the corresponding ^2! O-hydroxy-21-carboxylic acid, i.e. the steroid compound of the Formula VI.

0 II ООН OH HC2OH H ‘L ' xj O ^ ' H (VI)

The steroids of formulas V and VI exist in the form of mixtures of 2Ού and 20 (- hydroxysteroids). The reaction of the steroid of formula III or IV or a mixture thereof with an inorganic cyanide catalyst, oxidizing agent, inert solvent, alcohol and organic acid the product of formula I. The product of formula I can be obtained by reacting a storoid 21-aldehyde of formula III or the corresponding steric 21-acetal of formula IV or a mixture thereof with a mixture (i) of an inorganic cyanide catalyst (e.g. an alkali metal cyanide such as potassium cyanide), (ii) - ^ o ^ ^^^ čnij ii ^ i ^ O 'agents such as heavy metal oxide, activated' carbon mangainičitého · oxide or lead dioxide, (iii) an inert solvent ¹ , for example, a halogenated hydrocarbon, dichloromethane or chloroform, (iv) a primary or secondary alcohol R1'-OH (throughout the text). ihlášky the symbol R refers to any group neterciámí R) and (v) acids, such as' acetic acid, which serves to neutralize · catalyst alkali metal cyanide.

The products of the above reaction correspond to the general formula VII.

The 20α-β-SS-ydrroysteirides of formulas (V) and (VI) can be oxidized to form the oxides of oxides (3h, 20 C, 4 4, 4 1). The therapeutics of the formulas VIII and IX.

Examples of suitable oxidizing agents include manganese dioxide and chromium dioxide. In effluxes where oxidized 20α-α-20β-3-cycloxysSeroids contain 11 / thihydroxyxy substitueinite, the resulting steroids of formulas VIII and IX are mixtures of 11 / hroxy and 11-ketosteroids.

-Obecného intermediate of Formula VIII can also be prepared by esterification answered and sieτolam 21-oxygen obecného- vzorce- IX [steodia formula IX can be prepared by the procedure described -shora -or alternatively ester saponification - ICI steroiúm correspond to 21 ^J Yssel ins of formula VIII) .

Another method for the transport of intermediates of formula (VIII), wherein R 1. - means a non-tertiary group consisting in the toanisesterification of another ester of formula (VII) or (VIII). The starting sterile is reacted with an appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxed or aluminum isopropoxide) or, preferably, in the presence of a cyanide ion source (e.g., an alkali metal cyanide such as sodium cyanide or potassium cyanide) formation of the transesterified product.

The steroid of formula (VII), (VIII) or (IX) above may be converted to the corresponding product of formula (I) by reaction with a benzocyclobenzene of formula X or with butadiene of formula XI

H 2 C = C-C = CH 2

Rz Rs (Xi), using a Dielt-Alder reaction.

Using the starting material of formula (X), the reaction can be carried out without a solvent or in an inert solvent, for example o-dichloro-benzene or allyl-benzene. Preferably, the reaction is carried out in an inert atmosphere at a temperature of up to the boiling point of the reaction mixture in a non-refluxing solvent. A free radical inhibitor may be added to the mixture.

When starting material XI is used, the preferred reaction catalyst is anhydrous aluminum chloride or anhydrous aluminum bromide. The reaction may be carried out in an organic solvent, for example halogenated. - a hydrocarbon, as in ΙΙοΜοιμοthan. The Diels-Alder reaction described above is highly selective and occurs exclusively at the double bond at the 16-position, even in the presence of the A ^M -3-keto function. In those cases where the butadiene is unstable in the presence of the L-bis-acid-type catalyst, Delsel-Alder is carried out. reactions in the presence of a free radical inhibitor at an elevated temperature.

If the steroid of formula (VII), (VIII) or (IX) contains an 11-hydroxyl group, it is desirable to protect this group before carrying out the Diels-Alder reaction. Although a number of different methods for protecting the functional groups at the 11-position are known in the art of steroid chemistry, it is a particularly suitable method of acylating said hydroxy groups. The acylation reaction may be carried out using an acid anhydride such as acetic anhydride in the presence of a Lewis-type catalyst such as boron trifluoride etherate.

Another method of preparing the products of general formula I esterified with an alkyl group having 1 to 10 carbon atoms having no tertiary character -or- an aryl group consists in transesterifying another ester of formula I.

react with the corresponding alcohol in the presence of a basic alkali oxide (e.g. sodium ethoxide or aluminum itopropoxide) or, preferably, in the presence of a source of cyanide ions (e.g. alkali metal cyanide such as sodium cyanide or potassium cyanide) , resulting in a transcription of the purified product.

The thiothroids of the formula I are useful anti-inflammatory agents for topical application, which can be used in the place of known glucocorticoids for the treatment of various diseases such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and ano-

geiniital pirurit. The steroids described can be administered in the form of conventional curls, lotions, lotions or sprays at a concentration of from 0.01 to 5.0% by weight, preferably from 0.025 to 2.0% by weight.

The invention is illustrated by the following examples, but the invention is not limited in any way.

Example 1

Methyleister G-fluoro-1 ', 5'-tetrahydro-11'-hydroxy-5'-dioxopregna-1'-diene [16,17,17-b] naphthalein-21-oic acid

A. 9-f-nor-11 β-h yd γ x у - 3,2 O-di oxopregine α-1,1,16-triene-21-carboxaldehyde and 9-fluoro-11 l-hydroxy- 21-dimethoxypregna-1 ', 4,16-triene-3,20-dione

1.7 g of 9-fluoro-11,21-dihydroxypregna-1,1,16-thirine-3,20-dione are dissolved in 300 ml of methanol under heating. the solution is cooled to the imistaneous temperature, 100 mg of copper (I) octoate are added thereto, and a stream of air is added to the solution while stirring. Based on monitoring by thin-layer chromatography, the starting material disappears after about 20 minutes, which becomes less polar. The reaction solution is evaporated in vacuo, the residue is washed successively with dilute ammonium chloride solution and water and dried. 1.9 g of a practically equinolar simele of the title aldehyde (as a hydrate) and the title acetal (as shown by the NMR spectrum) are obtained. After drying for two hours at 67 Pa at 125 DEG-130 DEG C., this material is converted to 1.77 g of a substantially equimolar mixture (as shown by NMR and IR spectra) of the title aldehyde and acetal.

B. 9-Fluoro-11/3-hydroxy-3,20-dioxoipreigna-1,1,16-trieno-21-oic acid methyl ester

To a stirred solution of 1.75 g of the mixture of aldehyde and acetal prepared in paragraph A, in a mixture of 109 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol, 4.0 g of activated manganese dioxide, 500 mg of potassium cyanide and 0.5 ml of glacial acid acetic. Examination of thin-layer chircimatography shows that in less than 1 _: 0 hours the starting material disappears from the reaction mixture, which becomes essentially a single, less polar compound. The reaction mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with several small portions of warm dichloromethane / methanol. The filtrate was combined with the washings and evaporated to a solid residue which was washed with water and dried. Crystallization from methanol / dichloromethane (evaporation of dichloromethane) gave 1.4 g of the title compound, melting at 284-286 ° C.

C. Meithylesteir l \ 2 \ 3 \ 44etrahyidro-110-

-hydroxy-3,20-dioxopeneana-1,4-dieno [16a, 17-b] inaphthalen-21-ynoic acid

A solution of 100 mg of 9-fluoro-11,11-hydroxy-3,20-dioxop'regna-1,4,16-trien-21-enoic acid methyl ester in 5.0 ml of benzocyloblobuitene containing 6.0 mg of 4,4'-thiOH-bis-6-tert-butyl-m-kiresol was stirred under nitrogen for 10 hours to precipitate solid material. Unreacted benzoicyclobutene was removed by vacuum distillation and the residue was crystallized from a mixture of methanol and dichloromethane (evaporating dichloromethane). Yield -názvu compound, melting at 325-326 C, ^Q (color .This starts from about 295 ° C).

Example 2

9-Fluoro-11-hydroxy ^; roxy-3,20-dioxo-regna-1,1,16-triemo-21-acid

A solution of 100 mg of 9-fluoro-1 H -hydroxy-3,20-d: oxoipregna-1,1,16-trieno-21-oic acid methyl ester (see Example IB) in a mixture of 15 ml of m-eithanol and 15 ml of tetrahydrofuran was combined with with 1.0 ml of 3 M sodium hydroxide was stirred under a nitrogen atmosphere for 2.0 hours, then the mixture was acidified with 5θ / o hydrochloric acid and evaporated. The residue was washed with water and crystallized from a mixture of chloroform and methanol. The title compound is obtained which, when heated to 400 ^DEG C., turns black but does not melt.

The stero'd of this example can be esterified in a conventional manner and then reacted with benzocyclobutene as described in Example IC to give the product of Formula I.

Example 3 9-Fluoro-11'-hydroxy-1,1'-2'-dimethyl-6'-O-dioxoipregna-1'-di-16 ', 17-d] cyclohexen-21-ynoic acid n-butyl ester

A. 9-Fluoro-11 / S-hydroxy-3,20-dioxoiprone-1,1,16-thiene-21-carboxaldehyde and 9-fluoro-11 ^, hydroxy-21-dimethoxypregina-1 , 4,16-triene-3,20-dione

1.7 g of 9-fluoro-11,21,2-dihydroxypregine-1,1,16-α-3,20-α are dissolved in 300 µl of methanol under heating, the solution is cooled to room temperature and added. 10 mg of copper (II) vinegar are added thereto and a stream of air is introduced into the mixture while stirring. After monitoring the thin layer chromatogirafies, after about 20 minutes, the starting material disappeared from the reaction mixture and passed to less polar compounds. The reaction solution was evaporated in vacuo, the solid residue was washed successively with dilute, ammonium chloride solution and water and dried. 1.9 g of a practically equimolar mixture of the title aldehyde (in the form of a hydrate) and the title acetal are obtained as indicated by the NMR spectrum of the product. After drying for 2 hours at a vacuum of 125 mbar at 125-130 [deg.] C., this material is converted to 1.77 g of a practically equimolar mixture of the above aldehyde and aicetal as shown by NMR and IC spectra.

B. 9-Fluoro-11H-hydroxy-3,2O-

The di-prenox-1,1,16-trieno-21-acids are obtained

To a solution of the aldehyde / acetal mixture prepared in paragraph A in a mixture of 100 µl of anhydrous dichloromethane and 20 ml of anhydrous methanol is gradually added 4.0 g of activated manganese dioxide, 500 mg of potassium cyanide and 0.5 ml of glacial acid. acetic. As can be seen from thin-layer chromatography, the starting materials disappear in less than 1.0 hours, which are converted to virtually only one less polar compound. The reaction mixture was filtered through a pad of diatomaceous earth, and the filter cake was washed with several small portions of warm dichloromethane-methanol. The filtrate is taken up with the washings and evaporated to a solid residue which is washed with water and dried. Crystallization of this material from methanol / dichloromethane (evaporation of dichloromethane) gave 1.4 g of the title compound, melting at 284-286 ° C.

C. Methyleste? 113'-acetyloxy-9-fluoro-3,20-dboxoipregn and -1,4,16 -1-phenoxy-21-acids

A solution of 400 mg of 9-fluoro-116-hydroxy-3,2,2-dox opregna-1,4,16-trifluoro-21-enoic acid methyl ether in a mixture of 9.0 ml of glacial acid. The mixture was stirred at room temperature for 24 hours. After addition of 300 mg of sodium acetate, the mixture was poured into 200 ml of ice-water with stirring. the solid product was filtered off and dried after washing with water. 400 mg of the title compound is obtained which, according to thin-layer ehiromatography, is only contaminated with traces of impurities. This material after recrystallization from ethyl acetate / hexane gave 350 mg of the title compound at 235 DEG-23 DEG.

D. Methylesiter LL6-acetyloxy-9 - luoir-l ', 2'-dimethyl-3,20-dirxr IP re GN - 1,4-dieno- [16 _<a, 17 d] cyklcihexen-21-oic acid

To a solution of 320 mg of 11-acetylxxy-9-fluoro-3,20-dixo-oxegegna-1,1,16-trienx-21-xyl acid-methyl ether in 25 ml of beechoyl dichloromethane containing 100 mg of aluminum chloride was added with stirring -0.25 ml of 2,3-diimethyl-1,3-butadiene. The mixture was stirred at room temperature for 1.5 hours, then poured into water and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulphate and evaporated. An amount of 300 mg is chromatographed on a 10 g silica gel column to give 265 mg of the title compound which, after crystallization from ethyl acetate / hexane, yields 160 mg of the desired product as crystals, m.p. Deň: 32 ° C.

E. 9-fluoro-113-hydroxy-1 ', 2'-dimethyl-3,20-di-opregna-1,4-dieno [16x, 17-d] cyclohexene-21-one to y · e sorry a solution of 235 mg and 113 methylesteiru acetylxxy-9-fluo-Γ, 2'-dimethyl--3.20 · drυPOpτegra - 4-ďerx [16Ύ ₁ 17-d-21 Ccykloιhexen <? ve of an acid in a mixture of 100 ml of 90% methanol and 10 ml of tetrahydrofuran containing 2.0 ml of 3M sodium hydroxide is stirred in a 60-70 ° C bath for 2 to 3 hours under a nitrogen atmosphere. C. The mixture was acidified with a minimum of 5% hydrochloric acid and evaporated in vacuo. The residue was treated with water and dried. 195 mg of the title compound are obtained. After crystallization from a mixture of chloroform and methanol, an analytical sample of the above compound is obtained, melting at (233-239 ° C).

F. N-9-Butylesteir flucr-llS'hydroxy-R, Z ^{<-dΊmethyl-third,} twenty-dioxoρregna-l, 4-dienc- [16th », 17-d] cyclohexene-21-oic acid

To a solution of 175 mg of 9-fluoro-113-hydroxy-1 ', 2 ' -dimethyl-3,20-di-hexyegegna-1,4-dlenox [16a, 17-d]; cyclohexyne-21-xylic acid in 40 ml Dichloromethane containing several of the methanol is added with an excess of an ethereal solution of diazobutane. After 5 minutes, the excess diazobutane is decomposed by the addition of a few drops of acetic acid, the solution is evaporated to dryness and the residue is crystallized from a mixture of acetone and hexane. 127 mg of the title compound melting at 209-211 ° C is obtained.

4

Octyl-1'-T (113,16a) -9-fluoro-1 ', 2', 3 ', 4'-tetrahydro-11-haloxyl-3, 20-dirxopropyna-1,4-dieno [16,17-b] phthalen-21-yl acids

A solution of 500 mg of (0,96-imine-1) 1-methyl-ethyl ester (11 / 3,16%) -9β-methyl-2,3,3,4-tetrahydro-11-hydroxy-3,20-dioxopregna-1, 4-dienx [16,17-b] naphthyl] -4- (2-carboxylic acid) and 40 mg of sodium cyanide in 40 ml of dry 1-xktano-o (distilled over calcium hydride) - in - nitrogen -míchá 1.5 hours at a temperature of 130- ^C ° C and the resulting solution evaporated in vacuo. the residue was dissolved in dichlxrmethano, washed · water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in a mixture of chloroform and hexane (7: 3) and chromatographed on a column of 20 g of silica gel.

Elution with chloroform / hexane (7: 3) afforded 485 mg (97%) of product which, after crystallization from acetone / hexane, gave 370 mg (74%) of the desired product, m.p. 215-216 ° C.

Analysis calculated for C37H47FO5:

C 75.22%, H 8.02%, F 3.22%; found:

C 75.34 0/0, H 8.23 F 3.21%.

Example 5

9-Fluoro-11/3-hydroxy-3,20-dioxopregna-1,4-dieno [16,4,17-d] cyclohexen-21-enoic acid 2,2-dimethylpropyl ester

RoiZitoik 25 mg methyl ester. 9-fluoro-11 H -hydroxy-3,20-dioxopregna-1,4-diemo [16a, 17-d] cyclohexein-21-acid in 2.0 ml dry dioxane containing 400 mg dry neopentyl alcohol. 1 and 5.9 mg of sodium cyanide, were heated under reflux for 2 hours under anhydrous conditions. The reaction mixture was cooled, poured into water and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from ethyl acetate / chloroform to give 23 mg of the title compound, melting with decomposition at 288 ° C (the color changed before melting point).

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of steroid [16β, 17-b] cyclohexene and tetirahydroinaphthalein-Z1-carboxylic acids, pregnane series, of formula I, wherein: X represents a hydrogen atom or a fluorine atom; R? and R 3 are each independently hydrogen, C 1 -C 4 alkyl or together with the double bond to which they are attached form a benzene ring and their esters, characterized in that the 21-hydroxy radical is first oxidized; a steroid of formula (II), wherein the individual symbols are as defined above, to the 21-carboxy group and then to the position 16,17 is intensified to 1 ohexane or thyroid on afta 1 e. a ring of formula wherein each general symbol is as defined above.