DE1173091B - Process for the production of new ester salts of the androstane series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German class: 12 ο - 25/04

Number: 1173 091

File number: C 23096IV b / 12 ο

Filing date: January 4, 1961

Opening day: July 2nd, 1964

The invention relates to a process for the preparation of new 3-mono-o- or -m-sulfobenzoic acid ester salts of 3 ^, 17 / S-dihydroxy-androstane and -Δ ⁵ -androstane compounds which have a saturated or unsaturated aliphatic hydrocarbon radical in the 17-position and are derived from therapeutically applicable inorganic or organic bases.

The new process products are characterized by a high anti-allergic or anti-anaphylactic effect. Are z. For example, if male guinea pigs are sensitized by subcutaneous administration of ovalbumin, intravenous administration of a second dose of ovalbumin after 3 weeks can trigger an anaphylactic shock that is usually fatal within 3 to 15 minutes. The test animals are treated with 17'-isobutyl-androstane - 3 / 3.1 Iß - diöl - 3 - ortho - sulfobenzoate - sodium (A), 17a - methallyl - Δ ⁵ - androstene - 3β, administered intravenously shortly before the trigger , 1 Iß - diol - 3 - ο - sulf sodium benzoate (B) and 17 »-isobutyl-androstane-3ß, 17 / S-diol-3-m-sulfobenzoate sodium (C) better protected from this shock than by applying the well-known anti-allergic steroids prednisone (D) or prednisolone (E); this can be seen clearly from the following table:

The products of the process can thus be used for the treatment of allergic diseases, e.g. B. from asthma or allergic dermatoses. The new ester salts obtained according to the process form stable, aqueous solutions which can be sterilized in the heat without decomposition.

The new compounds are obtained when the 3-position hydroxyl group of a 3 / ?, 17 / S-dihydroxy-androstane or -Δ ^B -androstane compound, which has a saturated or unsaturated aliphatic hydrocarbon radical in the 17-position, is obtained in a manner known per se , with a reactive derivative of 0- or m-sulfobenzoic acid in the presence

preparation Dose i. v. Interval before
Shock release At least
two-thirds
survivors mg / kg hours Animals = + A. 30th 3 + B. 30th 3 + C. 30th 3 + D. 30th 5 _- E. 30th 3 r-. Con trolls - -. O

Process for the production of new ester salts
the androstane series

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dipl.-Ing. E. Splanemann, patent attorney,

Hamburg 36, Neuer Wall 10

Named as inventor:

Dr. Albert Wettstein, Riehen,

Dr. Georg Anner,

Dr. Ludwig Ehmann, Basel (Switzerland)

Claimed priority:

Switzerland of January 14, 1960 (375)

means of a basic agent and esterified the 3-mono-sulfobenzoic acid ester obtained, or a obtained Salt of the same, if necessary, with a therapeutically applicable inorganic or organic one Base implements.

The process-related esterification takes place in the presence or absence of a suitable diluent, z. B. a halogenated hydrocarbon such as methylene chloride or chloroform, and in the presence a basic agent, e.g. B. a tertiary amine such as pyridine, triethylamine or dimethylaniline. The reactive derivative of o- or m-sulfobenzoic acid is used, for. B. their anhydride or Chloride.

To prepare the desired salts, for. B. an aqueous solution of the obtained 3 / ?, 17 /? - dihydroxy-3-0- or -m-sulfobenzoate or its pyridine salt with an alkali or alkaline earth metal, in particular with Sodium, potassium, lithium, ammonium, calcium, strontium or magnesium hydroxide, carbonate, bicarbonate or halide or reacted with an amine. Suitable amines are aliphatic and cycloaliphatic or araliphatic amines with 1 to 8 carbon atoms and heterocyclic amines, ζ. Β. Mono-, di- and triethylamine, mono-, di- and trimethylamine, mono-, di- and triisopropylamine, Ethyldimethylamine, benzyldiethylamine, cyclohexylamine, dibenzylamine, Ν, Ν-dibenzylethylenediamine, Methoxyphenylisopropylamine, piperidine, morpholine,

4M 628/334

Pyrrolidine, piperazine and lower alkyl derivatives thereof, such as 1-methyl-piperidine, 4-ethyl-morpholine, 1-isopropyl-pyrrolidine, 1,4-dimethyl-piperazine, 1-n-butylpiperidine, 2-methyl-piperidine or l-methyl-2-methylpiperidine, also amines with water-soluble or hydrophilic groups, such as mono-, di- and triethanolamine, Ethyl diethanolamine, N-butylmonoethanolamine, 2-amino-1-butanoI, 2-amino-2-ethyl-1, 3-propanediol, 2-Amino-2-methyl-1-propanol, phenylmonoethanolamine, p-tert.-amylphenyldiethanolamine, galactamine, N-methyl-glucamine, N-methyl-glucosamine, ephedrine, Phenylephedrine, epinephrine, procaine, 2- (4'-tert-butyl-2 ', 6'-dimethyl-phenylmethyl) -imidazoline.

Of the products of the process, the following should be mentioned in particular: the sodium and potassium salts of 17 * -methyl-androstane-3 / 3.17β -diol-3-ortho-sulfobenzoate, 17-ethyl-androstane-3 / 3.17 / 3 -diol-3-ortho-sulfoate, 17α-propyl-3 / ?, 17β-diol-3-ortho-sulfoate, 17 * -isobutyl - androstane - 3 / 3.17 / 9-diol - 3 - ortho - sulf tossoate,

benzoate and the corresponding meta-sulfobenzoates and the Zl ⁵ derivatives.

The hydrocarbon radical is in the starting materials, which can be prepared in a manner known per se in the 17-position a saturated or unsaturated aliphatic hydrocarbon radical, e.g. B. a methyl, ethyl, propyl, isobutyl, vinyl, allyl, methallyl or ethynyl radical. The starting materials with a methallyl or isobutyl radical in the 17-position are new. Their production is detailed in the examples described.

The following examples explain the process according to the invention. The temperatures are in Degrees Celsius. Thin-layer chromatograms (DChr) are carried out on silica gel according to E. S t a h 1, Chemikerzeitung, Vol. 82, No. 10, p. 323 (1958); each 2Oy steroid are applied in 1% dioxane solution.

dried. DChr. Dioxane-water (9: 1), 62 resp. 58 mm from the starting point compared to 72 mm starting material.

Example 2

3.20 g of 17 \ -ethyl-androstane-3p>, 17/3-diol are in 80 ml of pyridine dissolved and after the addition of 2.76 g of o-SuIfobenzoic anhydride under nitrogen and Stirring heated to 90 ° for 100 minutes. The o-sulfobenzoic anhydride is almost completely in Solution. After 100 minutes, no 17-ethyl-androstane-3 / 3,17 / 3-diol can be found in the thin-layer chromatogram recognize more. The reaction mixture is cooled, filtered blank and completely evaporated in vacuo. The residue is dissolved in 500 ml of water while warming on a water bath, filtered and concentrated in vacuo to 150 ml. After standing overnight, the crystals are filtered off with suction and washed with water and dried. 3.32 g of the pyridine salt of 17-ethyl-androstane-3 / ?, 17/3-diol-3-o-sulfobenzoate are obtained. As described in Example 1, this is converted into the corresponding sodium salt. DChr. Dioxane — water (9: 1), 65 mm from the starting point compared to 80 mm starting material.

45

example 1

3.04 g of 17 "-Methyl-Zl ⁵ -androsten-3 / 3.17 / 3-diol are dissolved in 80 ml of pyridine and after adding 2.76 g of o-sulfobenzoic anhydride under nitrogen and stirring for 30 minutes to 90 ° heated. Another 0.27 g of o-sulf benzoic anhydride is added and the mixture is heated to 90 ° for a further 30 minutes; thereafter, no more 17 * -methyl-Zl ⁵ -androsten-3 / S, 17 /? - diol can be detected in the thin-layer chromatogram. The reaction solution is cooled and completely evaporated in vacuo. The crystalline residue is dissolved in 1500 ml of water, filtered and concentrated in vacuo to 100 ml. The product which crystallizes out after standing overnight is filtered off with suction, washed with a little water and dried in vacuo at 60 °.

Example 3

3.44 g of I7 \ -Methallyl-.J ⁵ -androsten-3 / 3.17 /? - dio] are dissolved in 40 ml of pyridine and after addition of 2.76 g of o-sulfobenzoic anhydride with stirring and in a nitrogen atmosphere for 30 minutes 90 ° heated. Most of the o-sulfobenzoic anhydride goes into solution. After 30 minutes, no more starting material can be detected in the thin-layer chromatogram. The reaction solution is cooled, the undissolved o-sulfobenzoic anhydride is suctioned off and the bright, orange-colored filtrate is completely evaporated in vacuo. The red-brown residue is taken up in 300 ml ( ⁿ / ₁₀ ) sodium bicarbonate solution with warming and salted out with 150 g of sodium chloride.

The precipitated product is filtered off with suction after standing overnight, washed with 30 ml of saturated sodium chloride solution and dried in vacuo at 60 to 70 °. 5 g of the sodium salt of 17 * -methallyl - Λ ⁵ - androstene - 3 / 3.17 / 3 - diol - 3 - ο - sulfobenzoate are obtained. DChr. Dioxane — water (9: 1), 60 mm from the starting point versus 75 mm from the starting material.

The raw material used above can be produced as follows:

128 g of magnesium chips are activated with 6 g of iodine and, after cooling, with 800 ml of tetrahydrofuran Doused over. Thereafter, first 40 ml of a mixture of 160 ml of tetrahydrofuran and 80 ml of methallyl chloride flow in and after the onset of the reaction within 30 minutes the rest of the

2.8 g of 17x-methyl- / | pyridine salt are obtained ⁶ -andro- 55 mixture. The low-boiling sten-3j8,17 (e-diol-3-o-sulfobenzoate. Solution is then dissolved within 165 minutes

In an analogous manner, m-sulfobenzoic acid chloride gives the pyridine salt of 17 «-methyl- / l ⁶ -androstene-3 / ?, 17/3-diol-3-m-sulfobenzoate.

2.8 g of the pyridine salts obtained are dissolved in 100 ml of water and first g of sodium bicarbonate and then 25 g of sodium chloride are added to the solution while stirring. The sodium salts formed precipitate here. They are filtered off, and saturated saline solution of 160 g / J ⁵ -androstenolone acetate and 480 ml of methallyl chloride are added dropwise to 2400 ml of tetrahydrofuran. It is rinsed with 240 ml of tetrahydrofuran and finally a further 140 ml of methallyl chloride is allowed to flow in within minutes to completely dissolve the magnesium. The reaction mixture is refluxed for a further 4 hours, then cooled and poured onto a mixture of 4000 g of finely crushed ice

washed, dissolved in 200 ml of water and discharged again with 65 and 1200 ml of 4N hydrochloric acid. One extracts

g salt out. The precipitated sodium salt of 17a-methyl-Zl ⁵ -androsten-3 / 3,17 /? - diol-3-o- or -3-m-sulfobenzoate is filtered off and in vacuo with ether and the ether extract washes repeatedly with 2N sulfuric acid, dilute bisulfite liquor, water, η sodium hydroxide solution and water,

dries over sodium sulfate and evaporates. The white crystalline residue (179 g) is fractionally redissolved from acetone and yields 131.5 g of 17x-methallyl- ^ l ⁵ -androsten-3 / 3.17 / S-diol. F. 169 to 170 °. [a]% ^fi ° = -50.1 ° (c = 0.979% in dioxane). S.

Example 4

52.2 g of 17oc-isobutyl-androstane-3 / S, 17 / S-diol are dissolved in 600 ml of pyridine. 41.4 g of o-sulfobenzoic anhydride are added and the mixture is heated to 90 ° for 60 minutes while stirring and in a nitrogen atmosphere. The reaction mixture initially turns slightly red-violet and finally orange, with the o-sulfobenzoic anhydride partially dissolving. It is then cooled to 20 to 25 °, the undissolved o-sulfobenzoic anhydride is suction filtered and this is washed out with 200 ml of pyridine. The filtrate is completely evaporated in vacuo at a temperature increasing successively to 80 °. 113.5 g of brown-orange-colored residue are obtained, consisting of the pyridine salt of 17'-isobutyl-androstane-3 / S, 170-diol-3-o-sulfobenzoate in addition to o-sulfobenzoic anhydride and the pyridine salt of o-sulfobenzoic acid. The evaporation residue is taken up in 2000 ml of water and neutralized with 21 g of sodium bicarbonate. The sodium salt of 17'-isobutyl-androstane-30,17 / 3-diol-3-o-sulfobenzoate partially crystallizes out. 300 g of table salt are added with stirring and suction filtered. The separated sodium salt is stirred with 2500 ml of water. A cloudy solution is obtained from which the sodium salt is salted out again by stirring in 500 g of sodium chloride. The precipitate is suction filtered and dried in vacuo at 60 to 70 °. The yield is 84.5 g of the sodium salt of 17'-isobutyl-androstane-3 / 3.17 / S-diol-3-o-sulfobenzoate, which contains some sodium chloride. For cleaning, the crude sodium salt obtained is dissolved in 1000 ml of fine spirits with warming, 2.5 g of filter asbestos are added and the mixture is filtered. The pure filtrate is concentrated to about 200 ml in vacuo, the sodium salt increasingly crystallizing out. After leaving to stand overnight, the product is filtered off with suction, washed with 40 ml of chilled fine spirits and dried in vacuo at 60 to 70 °. The yield is 72.5 g of the pure sodium salt of Na-isobutyl-androstane-S / ^ n / S-diol-So-sulfobenzoate. F. 220 to 223 °. [«] F ^s ° = + 2.5 ° (c = 2.00% in 25% aqueous alcohol).

Elemental analysis (post-dried at 100 °, 0.01 mm Hg)

for C ₃₀ H ₄₃ O ₆ SNa

Calculated ... C 64.96, H 7.81, Na 4.15%; Found ... C 64.6, H 8.0, Na 4.4%.

The raw material used above can be produced as follows:

a) 268.1 g of 17a-methallyl- / l ⁵ -androsten-3 / S, 17jß-diol are dissolved in 7000 ml of fine spirits and after the addition of 40 g of a 5% palladium-carbon catalyst at 20 to 25 ° and light Shaken with hydrogen at overpressure. The hydrogenation is complete after 8 hours. After adding 10 g of filter asbestos, the catalyst is filtered off with suction, the solution is stirred with 10 g of decolorizing charcoal for 10 minutes and filtered until it is clean. The solution is concentrated to 21 under a slight vacuum, cooled and, after standing overnight at 0 °, the crystals are filtered off with suction. The product is carefully washed with 150 ml of ice-cold fine spirits and dried in vacuo at 60 to 70 °. 106.4 g of 17'-isobutyl-androstane-3 / ?, 17/3-diol, which melts at 180 to 182 °, [α] f = -1.0 ° (c = 1.034% in dioxane) are obtained.

After concentration, further amounts of 17a-isobutyl-androstane-3jö, 17/3-diol, which melts at 168 to 169 °, are obtained from the mother liquors. [a] f = ± 0 ° (c = 1.00% in dioxane).

b) 6.8 g of 17 "-methallyl-Zl ⁸ -androsten-3 ^, l7j8-diol are dissolved in 100 ml of pyridine and, after the addition of 20 ml of acetic anhydride, left to stand for 52 hours at 20 to 25 °. The yellow-brown reaction solution is completely evaporated in vacuo, the residue is dissolved in ether and washed in sequence with 2N hydrochloric acid, water, 2N soda solution and water, dried and evaporated again. 7.3 g of white, crystalline residue with a melting point of 138 ° to 139 ° are obtained, which, after recrystallization from methanol, melts at 140 ° to 141 °. The yield is 6.6 g of 17 «-methallyl - Δ ^B - androstene - 30.17 / 3 - diol - 3 - acetate. [«] % ° = -50.6 ° (c = 1.00% in dioxane).

3.87 g of 17 "-methallyl-I ⁵ -androstened-30,17 / 3-diol-3-acetate are dissolved in 120 ml of fine spirits and, after three times, 0.5 g of a 5% palladium-carbon catalyst has been added Shaken with hydrogen at 20 to 25 ° and slightly overpressure. The hydrogenation is complete after 35 hours. The catalyst is separated off, the bare solution is completely evaporated and the residue is recrystallized from methanol. 2.12 g of 17a-isobutyl-androstane-3 / ?, 17/3-diol-3-acetate, which melts at 80 to 81 °, are obtained. [*] b = -7.7 ° (c = 1.168% in dioxane).

8.7 g nÄ-isobutyl-androstane-Sftn / S-diol-S-acetate are dissolved in 200 ml of methanol and, after adding 10 ml of 10N potassium hydroxide solution, reflux for 30 minutes cooked. It is diluted with water, the precipitated product is taken up in ether and this is washed in sequence after with dilute hydrochloric acid and water, dried over sodium sulfate and evaporated. The residue is recrystallized from fine spirits and yields 6.3 g of 17 "-isobutyl-androstane-3j5,17j8-diol, which at 180 to 183 ° melts.

Example 5

Analogous to the information in the preceding examples, starting from 17a-propyl-androstane-3 / S, 17/9-diol, the sodium and potassium salt of 17a-propyl-androstane-3 (3,17 ^ -diol-3-o-sulfobenzoates produce. DChr. Dioxane-water (9: 1), 70 mm from Starting point, starting material in the solvent front.

Example 6

34.86 g of 17 "-isobutyl-androstane-3 ^, 17 ^ -diol become dissolved in 400 ml of pure, dry pyridine. 25.0 g of m-sulfobenzoyl chloride are added and the mixture is stirred at 20 up to 40 ° internal temperature under nitrogen for 30 to 40 hours up to the thin layer chromatogram (System dioxane-water [9: 1]; indicator 50% Sulfuric acid) no free 17 "-isobutyl-androstane-3 / 3.17 /? - diol can prove more. The reaction solution is then successively in vacuo evaporated completely with increasing bath temperature. The dark-colored residue is dissolved in 1000 ml Water, neutralized with 10 g of sodium bicarbonate and, while stirring, 250 g of table salt are added, the Sodium salt of 17'-isobutyl-androstane-3j9,17j9-diol-3-m-sulfobenzoate fails. The mother liquor is separated off and the sodium salt in 2000 ml of water

recorded. A cloudy solution is obtained from which the sodium salt of 1 7.x - isobutyl - androstane - 3 / 3.1 7β - diol - 3 - m - sulfoboate is salted out again by stirring in 400 g of sodium chloride. The precipitate is sucked off and dried in a vacuum. The yield is 42.1 g of the sodium salt of 17 * -isobutylandrostane-3 / 9.17 | ß-diol-3-m-sulfobenzoate. DChr. Dioxane — water (9: 1), 55 mm from the starting point compared to 80 mm starting material.

IO

Claims (2)

Patent claims: 1. A process for the preparation of new ester salts of the androstane series, characterized in that the 3-position hydroxyl group of a 3ß, l7ß-di hydroxy-androstan- or -zl ⁵ -androstane compound which is saturated or in the 17-position is in a manner known per se unseeded has a saturated aliphatic hydrocarbon radical, with a reactive derivative of o- or m-sulfobenzoic acid in the presence of a basic agent esterified and the obtained 3-mono-sulfobenzoic acid ester, or a obtained Salt of the same, if necessary, with a therapeutically applicable inorganic or organic one Base implements. 2. The method according to claim 1, characterized in that the starting materials used are those 3 / ?, 17 /? - dihydroxy-androstane or -Δ ⁵ -androstene, which in the 17-position is a methyl, ethyl, propyl, isobutyl - or have methallyl radical. Considered publications:
German Auslegeschrift No. 1 072 243;
Journ. Org. Chem., 22, 473-475 (1957). 409 628/334 6.64 © Bundesdruckerei Berlin