DE1468945A1 - Process for the production of new steroid esters of the pregnancy series - Google Patents

Description

ROrjSSEL-UCLÄ] ?, Paris, France

Process for :: Manufacture of new steroid meters ö.e: i * Fregwanreike

The inventions *; "never concerns a method of manufacture Steroid esters of the Pregnan series, to which the general l'Oxiid comes to: O

3H ₂ -OC-OH ₂ - (O _{-CH 2 -CiI 2} ) _n ~ OC ₃ B _p

where St is a steroid, R is a hydrogen atom, an OH- or OR'-tiruppe, R * a Hiedrigacylrest and η the ZatJ. 1 or 2 mean, β ο as * in a process for manufacture; vox. their mixtures.

The new compounds have interesting pharmacodynamic properties Properties.

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Among the products available according to the invention there is the the following compounds are of particular interest:

21- (ß-Xthoxy-ß-ethoxy-ethoxy) acetate of 3,20-dioxo-11ß, 17a _f 21-taihydroxy-9c £ -: fluoro-16 "-" ethylpregna-1,4-diene "21 - (ß-Ithoxy-ß-ethoxy-ethoxy) acetate of frednisolone and 21- (ß-Xthoxy-ethoxy) acetate of 3,20-dioxo-11ß _f -Sfct-fluoro-1 est-methylpregna-1,4 -d iene.

When administered percutaneously, these compounds are effective against inflammation and against itchy leaf addiction.

Such esters are already known from DAS 1 156 075. However, these esters are soluble in water * while the compounds obtainable by the process according to the invention are water-insoluble.

As a result, the compounds of the formula I differ from the compounds of the abovementioned DAS by different physical properties. Their lack of moisture in water prevents diffusion or too rapid passage through the dermis. As a result, the effect of the compounds obtainable according to the invention is essentially noticeable on the level of the building, while the water-soluble substances act on general beds and consequently have the less undesirable secondary effects of hormone therapy.

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For example, the cortisone derivatives with the difficulties associated with a general effect of these derivatives are avoided. This prevents the appearance of the Lean, decalcification or corticotherapy the risk of relapsing gastric ulcer.

So one also avoids in the special case of the estrogenic Difficulties associated with a general action of these derivatives. As a result, the occurrence of mastopathies and feminization symptoms peculiar to ostrogen therapy «prevented.

The water-insoluble compounds obtained by the process according to the invention act practically only on external ones Injuries to be treated locally.

The process for making the new compounds of formula I, which is the subject of the invention, is characterized in particular by the fact that a 20-0xo-21-hydroxysteroid Pregnancy of the general formula

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- 4 -in position 21 with an organic acid of the formula

or with a juncture * derivative of the latter, where St,

R and £ the o '. * Er> given meanings are esterified t / ird.

A localized implementation of the inventive Verfrjvens relates in the use of the acid chloride as Fanktionel'es Der.trat the chosen organic acid and Un work in a tertiary amine, like pyridine.

Another / uBftihrtmgeform of erfindungßgeraäßen method is dt.rin, clocks the esterification with the anhydride of the selected organic acid duroheul * and _s Pyridij :, au work in a tertiary Amir like.

The following examples are used to provide a better understanding of the Invention. In these examples, the invention by the preparation of the 21- (ß-ethoxy-ß-ethoxy-ethoxy) acetate of the 3,20-Dioxo-11ß, 17oi, 21 ~ trihydroxy-9 «^ fluoro-16« "methylpregna-1,4-diene, of 21-Cß-ethoxy-ß-ethoxy-ethoxy) acetate des Prednisolone and the 21- (ß-ethoxy-ethoxy) -acetate des 3,20-Sioxo-11 £, 17 *, 21-trihydroxy-aa-fluoro-1 eec-methylpregna-1,4-tflen · veraneohaulloht “She is Je do oh of course not on theee limited to three examples.

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The same can be said of the acids mentioned above general formula other steroids, such as cortisone, hydrocortlson, Esterify prednisone, 9 ° i-sluorprednisolone, 3,20-dioxo ~ 11 ~, 17 *, 21-trlhydroxy-6rf ~ methylpregna-1,4-diene, etc.

Example 1 »Preparation of 21- (ß-ethoxy-ß-ethoxy-ethoxy) · acetate of 3,20-dioxo-Hß, 17 ^Ä _f 21-trihydroxy-fluorine-16 * -methylpregna-1,

1) is brought 11.5 g of sodium in 100 ml of Monoäthylather Bläthylenglykol and heated for several hours with stirring and Stlckstoffatmosphäre to an internal temperature of 150 ⁰ C to complete dissolution of the aur Satriums.

After cooling, 200 ml of benzene are added, then added in small portions 66.5 g of anhydrous potassium monochloroacetate and heat the reaction mixture for three hours with vigorous stirring to reflux.

It is then cooled, diluted with water, through Acidified addition of concentrated hydrochloric acid, the benzene phase decanted and the aqueous phase extracted with benzene.

The combined organic phases are dried, concentrated in vacuo to a small volume and then is the liquid residue is rectified in vacuo, the fraction which passes at 138 to 142 ° C./0.5 mm being recovered.

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The liquid thus obtained is put into X thy lace tat "at Dissolved at room temperature, saturated with a dimethylaminetrom (to destroy excess chloroacetic acid) Solution evaporated in vacuo.

The residue is taken up in water, acidified by adding hydrochloric acid and extracted with methylene chloride, the organic phase is recovered, dried, the solvent expelled, the residue rectified in vacuo and 22.7 g of (ß-Xthoxy-ß-ethoxy-ethoxy) acetic acid are obtained,

* ¹⁴² ° ^{C n}

0.5 mm ^β

The product is soluble in water, dilute aqueous alkalis and most common organic solutions average.

Analysis: ^c s ^H 16 ° 5 * Calculated} C £ 49.99 H £ 8.39 Found: 50.3 8.5

The compound has not yet been described in the literature.

2) 10 g (ß-ithoxy-ß-ethoxy-ethoxy) -acetic acid in 20 ml Thionyl chloride is introduced and the resulting solution is left to stand overnight at room temperature. Then it will be the excess thionyl chloride is drawn off under reduced pressure and the remaining liquid is in the Vacuum rectified.

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One gets the at 106-108 ⁰ C / 3mm fraction passing over and receives according to a second rectification of the same type 6.5 g (.beta.-ethoxy-.beta.-ethoxy-äthoxyJ-acetyl chloride from ^{β 108} ° ^{Ci n}

The product is colorless and soluble in chloroform. Analysis: CgH ₁ COjCl = 210.6 Calculated: C 45.61 # H 7.18 56 Cl 16.83 #

Found: 45.9 7.20 17

The connection has not yet been found in the literature described.

At a temperature of 0 ⁰ C brings to 10.3 g of 3,20-dioxo-11 SS, *, 21 trihydroxy-9a-fluoro-1ftt-methylpregna 1 ₁ 4-diene in 52 ml of anhydrous pyridine and 17 are then slowly a solution of 6.2 g of (β-ethoxy-β-ethoxy-ethoxy) acetyl chloride in 25 ml of chloroform and the reaction mixture is allowed to stand on ice for 60 hours.

Then add a few drops of water, stir and then poured into water, decanted off the organic phase and extracted the aqueous phase with chloroform.

The organic phases are combined, one after the other with Water, 5N hydrochloric acid, water, with a sodium bicarbonate solution and finally with water until the

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Wash water washed.

Dry, concentrate in vacuo, take what remains Oil with methylene chloride and chromatographyert the obtained Solution over aluminum oxide, eluting with methylene chloride. The eluate is concentrated to dryness and the remaining oil is dissolved in 30 ml of ethyl acetate. Then you give 135 ml Xther to, rub to crystallize and leave a compartment at room temperature.

It is then filtered off with suction, dried in vacuo and 8.5 g of the 21- (ß-Ä "thoxy-ß-ethoxy-ethoxy) acetate des 3.20-dioxo-11ß, 17 <*, 21-trihydroxy-9 are obtained "I-fluoro-16Ä-methylpregna-1,4-diene from P. 119 ⁰ C / ei / | °" + 72.8 ° + 1 (c _s 1 Ji in dioxane).

The product is obtained in the form of colorless prisms in water and Xther are insoluble, soluble in alcohol, acetone, benzene and chloroform.

Analysis: C3o ^H 43 * ° 9 ^{m 566f64} Calculated: C 63.58 # H 7.65 1> P 3.35 %

Found: 63.7 7.6 3.6

The compound has not yet been described in the literature.

Example 2: Preparation of the 21 ~ (ß-Ä * thoxy-ß-ethoxy-ethoxy) ~ acetate of prednisolone.

You work as described in the previous example and

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I 4DO3HO - 9 -

receives a product based on prednisolone which is obtained in the form of colorless prisms which are soluble in alcohol, acetone, benzene and chloroform and insoluble in water and ether · P * 142 ⁰ C ₁ / cc / £ ° m + 94 ° (approx £ 1 in dioxane).

The 21- (ß-ethoxy-ß-ethoxy ~ ethoxy) acetate dee Prednisolone has not yet been described in the literature.

Example 3; Preparation of the 21- (β-A * thoxy-ethoxy) ~ acetate dee 3,2 (KDiOXo-11β, 17o ^ 21-trihydroxy-9ot ~ fluoro-16Ä-methylpregna-1,4-diene.

A Hers tel development of Reagent:

1) is brought 17.25 g of sodium in 125 ml of ethylene glycol monoethyl ether and heated to a Innenteraperatur of 100 to 110 ⁰ C, is completely dissolved until the sodium. After cooling, 300 ml of anhydrous benzene are added and 100 g of potassium raonochloroacetate are then added in small portions over the course of half an hour, and the reaction mixture is refluxed for three hours with vigorous stirring.

It is then cooled, water is added, acidified by adding concentrated hydrochloric acid, and the benzene phase is decanted and extracted the aqueous phase with benzene.

The organic phases are combined, dried, concentrated in vacuo to a small volume and then rectified the liquid residue in vacuo and wins the at

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120-127 ° C / 3mm passing fraction, 32.3 g (ß-Ethoxy-afchoxyJ-ensetic acid receives / iieho Palomaa and Ooll .; Reports 6Ji, 3117 (193OjJ, which raan ale such. For the further manufacture used.

The liquid is colorless and soluble in water and most common organic solvents.

2) 14 g of Cβ-ethoxy-ethoxy) acetic acid, which was prepared as described above, is added to 28 ml of thionyl chloride and the resulting solution is left to stand for one night at room temperature. Excess thionyl chloride is then expelled under reduced pressure and the liquid residue is rectified in vacuo. The fraction that passes over at 85 - 87 ⁰ C / 14 km is obtained. After a second of the same kind. Rektlfijsierung obtained 11.2 g (ß-ethoxy-äthoxyJ-acetyl chloride by the K ^ ₂₀ - 91-93 ⁰ C; n ^ ° "1.4360.

The product is colorless and in ether, benzene and chloroform soluble.

Analysis: G ₆ H ₁₁ ClO ₅ * 166.61

Calculated "C $ 43.25 H 6.66 % Gl $ 21.28> Found: 43.4 6.7 21.3

The connection has not yet been found in the literature described.

At a temperature of 0 ⁰ C bringing 10 g of 3,20-dioxo-11.beta. ~

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17oo, 2i-trihydroxy-9 ^Ä ~ fluoro-16 "Umethylpregna-i, 4-dien one in 50 ml of anhydrous pyridine and thereafter a solution was added dropwise 4.7 g (ß-Xthoxy-ethoxy) -acetyl chloride in 20 ml of anhydrous Chloroform ssu and the reaction mixture is left to stand on ice overnight.

Then a few drops of water are added, stirred, then poured onto water, the chloroforms cht and decanted extract the aqueous layer with chloroform.

The combined organic phases are successively with water, 5N hydrochloric acid, water and sodium bicarbonate solution and Finally washed again with water until the wash water is neutral.

! Then it is dried, concentrated in vacuo to a small volume, the residue taken up in methylene chloride and the resulting solution chromatographed over aluminum oxide under Elution with methylene chloride.

It distributes the Lesungemittel in vacuo, crystallized from warm Bexusol, thus obtaining 9 g of 21- (beta-Xthoxy-ethoxy) -acetate of the 3,20-dioxo-11β, 17 * -> 21-trihydroxy - ^^ - fluoro- 1 6ä-

aetnylpregna-1,4-diens from 7 172 ⁰ C; / * / jj ° _β + ao 2 ° (c - 0.5 1 ° in dioxane).

The product is obtained in the form of colorless crystals, the In Water, dilute aqueous acids and alkalis insoluble,

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are sparingly soluble in ether and benzene and soluble in alcohol and chloroform.

Analysis: C ₂₈ H ₃₉ PO ₈ ■ 522.59

Calculated: C 64.35 # H 7.52 # F 3.64 # Found: 64.6 7.6 3.7

The compound has "not yet been described in the literature.

VIe already stated above, the steroid esters have the general formula I interesting pharmacological properties.

For example, 21- (ß-ethoxy-ß-ethoxy-ethoxy) acetate has of 3,20-Dioxo-11 ß, 17 *, 21 -trihydroxy-9 # -fluor-16 # - methylpregna-1,4-diene has a strong anti-inf laminator effect and a strong action against itch leaf requests. It can but treatment of inflammatory affections, infectious Dermatoses, itchy leaf addiction, eczema and sores ▼ can be used.

The esters of general formula I such as 21- (ß ~ ethoxy-ßäthoxy-ethoxy) acetate des 3,20-Dioxo-11β, 17 *, 21-tr! hydroxy-9etfluoro-16ot-methylpregna-1,4-diene are applied locally by topical application to the skin and mucous membranes.

They can be in the form of vaginal jellies, ointments, creams, and jellies.

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Pharmaceutical forms such as ointments, crimes, and jellies are made by the usual methods

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Claims (3)

U68945 claims 1. Process for the production of new steroid ethers of the Pregnan range with the general formula: H ₂ -O-CH ₂ - (0-CH ₂ -CH _{2) n} ~ 0C2 ^H 5 .0 wherein St is a steroid radical, R is a hydrogen atom, an OH or OR 'group, R ^{1 is} a lower acyl radical and η is the number 1 or 2, characterized in that in position 21 a 20-0x0-21-hydroxysteroid of the pregnane series is used of the general formula: ^ Organic acid bit of the general formula C ₂ H ₅ O- (CHgCH ₂ -O) _n -CH ₂ -C ^ OH or a functional derivative of the latter, where £ t _f R ORIGINAL INSPECTED 909806/1069 U68945 and η have the meaning given above, esterified. 2. The method according to claim 1, characterized in that ■ as a fractional derivative of the selected organic Acid uses the acid chloride and works in the presence of a tertiary amine, especially pyridine. 3. The method according to claim 1, characterized in that the anhydride is used as the fractional derivative of the chosen acid and in the presence of a tertiary amine, especially of pyridine, works. 909806/1069