CA1058161A - 3,20-DIKETOPREGNENES HAVING AN 11.beta.-ACETAL GROUP AND DERIVATIVES THEREOF - Google Patents

Abstract

ABSTRACT
3,20-Diketopregnenes having in tho 110-position a group of the formula

Description

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~ Hydroxy-3,20-diketopregnenes having a cyclic 16,17-acetal or ketal group are well known and widely used anti-inflammatory agents. Exemplary of this type of steroid are halcinonide (21-chloro-9-fluoro-11~-hydroxy-2',2'-dimethyl-pregn-4-eno[16~,17-d][1,3]dioxolane-3,20-dione) and triam-cinolone acetonide (9-fluoro-11~,21-dihydroxy-2',2'-dimethyl-pregna-1,4-dieno [i6a,17-d][1,3]dioxolane-3,20-dione). The limited solubility of these pregnenes in slightly polar solvents such as ether leads to problems in formulation design.
In order to ease the problems of formulating 11~-hydroxy-3,20-diketopregnenes having a 16,17-cyclic acetal or ketal group (and in order to prepare new and useful anti-inflammatory agents), the prior art has prepared ll-keto and ll-acyloxy steroids. While these modifications do increase the solubility of the steroids, they generally result in steroids of lesser activity.
The prior art also shows that some steroids having 11-acetal groups have been prepared. For example, Fukushima et al., J. Org. Chem., 26, 520 (1961) disclose the formation of ll~-(methoxymethyl)-17,20;20,21-bismethylenedioxypregn-4-ene-3-one as a by-product during the reaction of hydro-cortisone with formaldehvde. Gardi et al., J. Org. Chem., 27, 668 (1962) and Tetrahedron, 21, 179 (1965), disclose - steroids having 17,21-cyclic acetal groups as substituents and in the ll-position a group of the formula I O - alkyl R- CH- O -wherein R is alkyl or aryl. r~

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It is an object of this invention to provide steroids having topical and systemic anti-inflammatory activity.
It is an object of this invention to provide steroids which can Be readily formulated in slightly polar solvents such as castor oil or propylene carbonate.
These, and other o~jects that will be readily apparent to a person of ordinary skill in the steroid art, are met by the steroids of this invention.
The steroids of this invention are those having the formula CH2-R
II OR

'~ --jl ~i ~oi R6 o and the 1,2~ and 6,7~defiydro deri~atives thereof; pregn~4~
enes and pregna-1,4~dienes are preferred. In formula II, and throughout the specification, the symbols are as deflned below.
Rl can be alkyl;
R2 can be hydrogen,~ alkyl, alkoxy, or halogen;
R3 can be hyd-rogen, acyloxy, halogen or hydroxy;
R4 can be hydrogen or halogen;
R5 can be hydrogen, alkyl, or aryl;
R6 can be a7kyl or aryl;
R7 can be hydrogen, fluorine, or methyl; and R8 can be hydrogen, chlorine, or methyl.

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The term "alkyL", as used throughout the specification, refers to straight or branched chain alkyl groups having 1 to 8 carbon atoms. Alkyl groups having 1 to 3 carbon a toms are preferred.
The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.
The term "acyloxy", as used throughout the specification, refers to groups wherein the acyl portion is a physiologically acceptable acid residue derived from an organic acid. Exemp-lary monocarboxylic acids are those having the formula Y-COOH
wherein Y is alkyl, cycloalkyl of 3 to 6 carbon atoms, aryl-alkyl or aryl; e.g., acetic, propionic, valeric, cyclohexane-carboxylic, phenylacetic, benzoic, and toluic acids. Exemp~
lary polycarboxylic acids are malonic, succinic, glutaric, adipic, pimelic and phthalic acids.
The term "aryl", as used throughout the specification, refers to phenyl or phenyl substituted with 1 or 2 alkyl, alkoxy, or halogen groups.
The term "alkoxy", as used throughout the specification, refers to a group having the formula alkyl-O-, wherein alkyl is as defined above.

The steroids of this invention are physiologically active substances which possess glucocorticoid and anti-inflammatory activity and hence can be used in lieu of known glucocorticoids in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same manner as hydrocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid. In addition, the steroids of this invention can be used topically in lieu of known glucocorti-coids in the treatment of skin conditions such as dermatitis, ~ K548 psoriasis, sunburn, neuro~ermatitis, eczema, and anogenitalpruritus.
When given orally, the compounds of this invention may be used in a daily dosage range of 0.1 to 200 milligrams per 70 kilograms, preferably 0.3 to 100 milligrams per 70 kilograms.
If administered topically, the compounds of this invention may be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream or lotion.
The 3,20 diketopregnenes of formula II, wherein R2 is ortho-alkyl, can be prepared ~y reacting an 11~-hydroxy-3,20-diketopregnene, i.e., an ll~-hydroxy counterpart of the steroid of Formula II with a l-alkoxybenzocyclobutene having the formula III ~ OR

~ R'2 wherein R2 is hydrogen or an alkyl group having 1 to 7 carbon atoms. The reaction, which is a novel one and constitutes a part of this invention, can be run under neutral conditions in an aprotic solvent, e.g. , a hydrocarbon such as benzene or toluene. While reaction conditions are not critical, the re-action will preferably be run at, or near, the reflux temperature of the solvent. This reaction is useful not only in the pre-paration of the steroids of this invention, but also in the preparation of other steroids containing an ll~-hydroxy group which must be protected during multi-step syntheses. The blocking group can be readily removed by acid hydrolysis.
The 3,20 diketopregnenes of formula II can be prepared by reacting an ll~-hydroxy-3,20-diketopregnene, i.e., an 11~-hydroxy counterpart of the steroid of formula II with a benz-aldehyde dialkyl acetal having the formula ~ 6 IV

OR

The reaction can be run in an aprotic solvent, e.~., a hydro-carbon such as benzene or toluene. The reaction is run under acid conditions (e.g., in the presence of an organic acid such as p-toluenesulfonic acid) and can be run at, or near, the reflux temperature of the solvent.
Many variations and modifications of this invention will be apparent to a person of ordinary skill in the field of steroid chemistry. If, for example, the ll~-hydroxv-3,20-diketo-pregnene used to prepare the-steroids of this invention contains additional hydroxyl groups, they should be protected before proceeding with the above-described reactions.
The following examples are specific embodiments of this invention.

~05~1~1 K548 Example 1 21-Chloro-11~-[ethoxy(2-meth lph~nyl)methoxy]-9-fluoro-2',2'-dimethylpregn-4-eno[16a,17-d~1,3]d~loxolane-3,20-dione~ ~~~

A suspension of 21-chloro-9-fluoro-11~-hydroxy-2',2'-dimethylpregn-4-eno[16a,17-dl[1,3]dioxolane-3,20-dione (684 mg) in anhydrous toluene (17 ml) containing 1-ethoxy-1,2-dihydro-benzocyclobutene (444 mg) is refluxed in a nitrogen atmosphere.
In a few minutes a homogeneous solution is obtained. After about 6 hours, the solution is cooled and then absorbed on a column of silica gel (20 g). Elution of the column with chloro-form-hexane (1:4) yields unreacted 1-ethoxy-1,2-dihydrobenzo-cyclobutene. Further eltuion of the column with chloroform-hexane (1:4 and 1:1) gives the product as a foam (0.90 g). This is dissolved in the minimum amount of ether, diluted with 10 ml of hexane and maintained at a temperature of about 5C to yield the solid (355 mg), melting point 171-180C. Recrystallization of this material from ethyl acetate-hexane yields the title compound (205 mg), melting point 182-185C.
Example 2 9-Fluoro-ll~-(methoxyphenylmethoxy)-2',2'-dimethy1pregna-1,4-dieno[l6,17-d)[1,3]dioxolane-3,20-dione A suspension of 9-fluoro-11~-hydroxy-2',2'-dimethyl-pregna-1,4-dieno[16a,17-d]~1,3]dioxolane-3,20-dione (1.0 g) and benzaldehyde dimethyl acetal (2.0 g) in benzene (130 mlj containing ~-toluenesulfonic acid (15 mg) is azeotropically distilled. After about 25 minutes, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried and evaporated in vacuo to yield a solid (1.3 g). Recrystallization of this .:
material from ethyl acetate-hexane yields the title compound (0.9 g), melting point 198-214C.

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Example 3 21-(Acetyloxy)-9~fluoro~ (methox henylmethoxy)-2',2'-d;methylpregna-1,4-dieno~16a,17-dJ ~,31dioxolane-3,20-dione A suspension of triamcinolone acetonide, 21-acetate (1.0 g~ in benzene (150 ml) containing benzaldehyde dimethyl acetal t2.0 g) and ~-toluenesulfonic acid (25 mg) i5 distilled removing the benzene. After about 30 minutes, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried using magnesium sulfate and evaporated to a solid which is absorbed on a column of silica gel (40 g). Elution of the column with chloroform-hexane (1:4) removes non-steroidal impurities. Further elution with chloroform-hexane (3:7 and 1:1) yields 0.96 mg of material which is recrystallized from ethyl acetate-hexane to yield the title compound (0~5 g), - melting point 196-198C.
Example 4 21-(Acetyloxv)-ll~-[ethoxy(2-methylphenYl)methoxy]-9-fluoro-

2',2'-dimethylpregna-1,4-dieno[r6a,17-d~[1,3]dioxolane-3,20-dione Triamcinolone acetonide, 21-acetate (1.0 g) is dissolved in anhydrous xylenes (37 ml) in an oil bath maintained at about 125C in a nitrogen atmosphere. l-Ethoxybenzocyclobutene (1.11 g) is added and after 18 hours the reaction is incomplete. The following additional amounts of l-ethoxybenzocyclobutene are added at the indicated time intervals:
0.3ml (21 hours) 0.3ml (24 hours) 0.3ml (28 hours) 0.3ml (46 hours) and 0.3ml (48 hours) The solution is evaporated and the residue is dissolved in chloro-form and chromatographed on a silica gel column (25 mg). Elution of the column with chloroform-hexane (1:4 to 1:1) removes non-l~)S~
steroidal impurities. Further elution with chloroform-hexane (4:1) and chloroform yield the desired material (0.8 g). The solid is dried to yield the title compound, melting point 105-11 0 C .
Exam~les 5-8 Following the procedure of Example 1, but substituting the steroid listed in column I for 21-chloro-9-fluoro-11~-hydroxy-2',2'-dimethylpregn-4-eno~16a,17-d][1,3]dioxolane-3,20-dione and the compound listed in column II for l-ethoxy-1,2-dihydro-ben7.ocyclobutene, yields the steroid listed in column III.

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~ r~ rt --~ ` ` ~ O ~ ~--1 105~16~ K548 xamples 9-11 Following the procedure of Example 2, but substituting the steroid listed in column I for 9-fluoro-11~-hydroxy-2',2'-dimethylpregna-1,4-dieno[16a,17-d][1,3]dioxolane-3,20-dione and the compound listed in column II for benzaldehyde dimethyl acetal, yields the steroid listed in column III.

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a~ o . X548 ~058161 Example 12 (methoxyphen lmethox )-2',2'-dimeth 1-re~na-1,4-di ~

A suspension of 21-(acetyloxy)-9-fluoro-11~-(methoxy-phenylmethoxy)-2',2'-dimethylpregna-1,4-dieno[16a,17-dl[1,3]-dioxolane-3,20-dione (0.7 g, prepared as described in Example 3) in 7s ml of methanol is cooled to OC and 7 ml of 10% potassium carbonate solution is added. After lS minutes, 20 mI of 20%
aqueous acetic acid is added followed by water, and the resulting solid is filtered and dried in vacuo.to yield the title compound.

Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE

PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a steroid of the formula or a 1,2- or 6,7-dehydro derivative thereof, wherein R1 is alkyl; R2 is hydrogen, alkyl, alkoxy or halogen; R3 is hydrogen, acyloxy, halogen or hydroxy; R4 is hydrogen or halogen; R5 is hydrogen, alkyl or aryl; R6 is alkyl or aryl;
R7 is hydrogen, fluorine or methyl; and R8 is hydrogen, chlorine or methyl, characterized by reacting a steroid of the formula with a benzaldehyde dialkyl acetal having the formula wherein R1 is alkyl, or with a 1-alkoxybenzocyclobutene of the formula wherein R1 is alkyl and R2 is alkyl.

2, A process in accordance with claim 1 wherein R4 is fluorine, R7 is hydrogen, and R8 is hydrogen.

3. A process in accordance with claim 2 wherein R5 and R6 are each methyl.

4. A process in accordance with claim 3 wherein R3 is hydrogen.

5. A process in accordance with claim 3 wherein R3 is acyloxy.

6. A process in accordance with claim 3 wherein R3 is halogen.

7. A process, in accordance with claim 3 wherein R3 is hydroxy.

8. A process in accordance with claim 2 wherein R2 is hydrogen or methyl.

9. A process in accordance with claim 3 wherein R2 is hydrogen or methyl.

10. The process in accordance with claim 1 wherein the product is 21-chloro-11.beta.-[ethoxy(2-methylphenyl)methoxy]-9-fluoro-2',2'-dimethylpregn-4-eno[16.alpha.,17-d][1,3]dioxolane-3,20-dione.

11. The process in accordance with claim 1 wherein the product is 9-fluoro-11.beta.-(methoxyphenylmethoxy)-2',2'-dimethyl-pregna-1,4-dieno[16.alpha.,17-d][1,3]dioxolane-3,20-dione.

12. The process in accordance with claim 1 wherein the product is 21-(acetyloxy)-9-fluoro-11.beta.-(methoxyphenyl-methoxy)-2',2'-dimethylpregna-1,4-dieno[16.alpha.,17-d][1,3]dioxolane-3,20-dione.

13. The process in accordance with claim 1 wherein the product is 21-(acetyloxy)-11.beta.-[ethoxy(2-methylphenyl)-methoxy]-9-fluoro-2',2'-dimethylpregna-1,4-dieno[l6.alpha.,17-d]-[1,3]dioxolane-3,20-dione.

14. A process for preparing a steroid having in the 11.beta.-position a group of the formula wherein R1 and R2 are the same or different and are each alkyl having 1 to 8 carbon atoms, which comprises reacting a 1-alkoxy-benzocyclobutene having the formula wherein Rl is alkyl having 1 to 8 carbon atoms and R2 is hydrogen or alkyl having 1 to 7 carbon atoms, with an 11.beta.-hydroxy steroid under substantially neutral conditions.

15. A process in accordance with claim 14 wherein R2 is methyl and R'2 is hydrogen.