DE1020976B - Process for the preparation of central nervous system calming steroid compounds - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of new water-soluble steroid compounds of following structural formula:

CH ₂

C = O

CH,

(I)

Alkoxy -.

which have no hormonal effects and are good central nervous system depressants.

This formula is intended to encompass both the compounds of the pregnan series and the allopregnan series. The alkoxy group at the 3-position can be in the a or the / 9 configuration.

In the above formula, E can mean an ionic ester group or a glycoside group. The expression vionic ester »denotes an ionic ester of formula

- OCLC ~ O "M ⁺

or the formula

_O —CL-NR ₃ ¹ Z "

Ii 0

in which L is either - (CH ₄ ) ,, -, - O- (CHj) _n - or --NH - (CH _a ) "-, η is a number from 1 to 6, M ^{+ is} one of the cations Na ⁺ , K ⁺ or NR ₄ ⁺ , each R is either hydrogen or an alkyl, oxyalkyl, hydrocarboxyalkyl, aminoalkyl, aryl or aralkyl group, each of which contains up to 10 carbon atoms, and Z is a pharmaceutically acceptable anion . The term "glycoside group" denotes a group derived from a monosaccharide pentose or hexose, disaccharides from pentoses or hexoses. Ionic ester groups and glycoside groups have the common property of making the compounds containing them water-soluble.
There are 4 possibilities for isomerism in ring A.
5-position alkoxy group

1. normal α configuration

2. normal / 3 configuration

3. Allo-form α-configuration

4. Allo-Form / 9 configuration

Method of manufacture

from on the central nervous system

calming effect

Steroid compounds

Applicant:

Chas. Pfizer & Co., Inc.,
Brooklyn, NY (V. St. A.)

Representative: Dr. W. Beil, lawyer,
Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
V. St. v. America May 16, 1955

Barry Malcolm Bloom, Jackson Heights, N.Y.,

Sanford Kermit Figdor, Forest Hills, NY,
and Gerald David Laubach, Jackson Heights, NY

(V. St. Α.),
have been named as inventors

The scope of the present invention encompasses all of these possibilities, and all of these compounds can be prepared from the known starting material J ^s -Pregnen-3 / 3,21-diol-20-one-21-acetate. To achieve the desired result, change the order in which the reactions are carried out.

The oxy group in the 3 /? Position of the starting material is converted to an alkoxy group by first converting it to a 3/9 tosyl (i.e. p-toluenesulfonyl) group convicted. This is done through treatment ζ. B. with p-toluenesulfochloride in the presence of pyridine. The alkoxy group is then obtained by treating the tosyl group in the 3 /? -position with a lower alkanol, e.g. methanol, ethanol or propanol, introduced into the 3-position. When this reaction is carried out in the presence of a 5-position double bond, the one which occurs Alkoxy group in the / ^ configuration. However, one leads the reaction after hydrogenation of the 5-position double bond off, the entering alkoxy group goes into the a configuration. Accordingly, the position of the alkoxy group becomes in the 3-position determined by whether the Replacement of the toxyl group by the alkoxy group is a 5-position double bond or not. Want one therefore has a 3 / tf alkoxy group, so leads if the alkoxy group is inserted before the hydrogenation of the 5-position, double bond, on the other hand, a 3'-position becomes

709 410/34!

If an alkoxy group is desired, the alkoxy group is introduced after this hydrogenation; otherwise remains the Reaction course the same. Ks should also be mentioned that during the reaction in which the tosyl group in the 3-Steüimg is replaced by an alkoxy group, in the case of starting materials which have an acyl group in the 21-position, e.g. as acetates, this group to an Oxygrtippc is hydrolyzed.

The hydrogenation of the double bond in the 5-position is achieved by using palladium on charcoal as a catalyst, the hydrogenation product predominantly consists of audio connection. It also educates however, there is always an isolable amount of the normal isomer. So always arise with the same reaction both isomers next to each other Each isomer is made out of the mixture by. Column chromatography or also separated by fractional recrystallization. A column is suitable for column chromatography Magncsiiunsilikat (known under the trade name Florisil), washed out with mixtures of benzo) and ether will.

After the hydrogenation step, the oxy group in the 21-position becomes an ionic ester or a glycoside converted. If a Henri succinate group was introduced before the hydrogenation, this hemisuccinate group can be used use directly to produce an ionic ester, e.g. the sodium salt.

The new compounds which can be prepared by the process according to the invention have properties which make them very valuable. They are soluble in water without Hormonal action, but effective as a sedative for the central. Nervous system. They are suitable as deafening, Antispasmodic, calming, pain reliever and sleeping pills. You can use them on their own or in conjunction with other tranquilizers for apply the central nervous system. They are so soluble in water that they can be administered intravenously in sterile aqueous solution can be injected. A particularly suitable method for sterilizing such an injection solution is the filtration through a Seitz filter. The compounds can also be used in aqueous solutions, which also contain other substances in dissolved form, e.g. enough salt or glucose to make them isotonic. they are also applicable in other ways, e.g. internally or by subeutane and intramuscular injection. the Verbmdimgen can be with a number of different pharmacologically acceptable additives are mixed, the choice of which depends on the desired method of application depends and is determined by standard pharmaceutical practice; the connections can, for example, be internal be given in the form of tablets containing an inert carrier, e.g. starch, or in the form of a Elixir or suspension in a carrier.

The examples explain the process according to the invention.

example 1

Zl ^r '-Pregnen-3 / 5,21-diol-20-one-21-acetate was reacted at room temperature with p-toluenesulfonyl chloride and pyridine to give the corresponding 3β-tosyl compound, which had the following physical constants: mp 113.6 bis 114.8 °; AIf; 5.73, 5.81, 6.25, 8.07.

1.43 g; d ⁵ -Prcgnen-3 / 3,21-diol-20-one-3-tosylate-21-acetate were ^{refluxed for 2 hours in 100 cm 3 of} absolute methanol with exclusion of moisture. 300 mg of potassium carbonate, dissolved in as little water as possible, were then added and the solvent was then removed. Trituration of the crystalline residue with water gave, after drying in vacuo over phosphorus pentoxide, a white powder which was found to be Zl ⁵ -pregnen-21-ol-3/3-methoxy-20-one with the following physical properties: mp 158 , 2 to 160.0 °; λ ™. 2.89, 5.91.9.12.

The hydroxyl group in the 21-position of this compound was treated with succinic anhydride

. ⁵ drid and pyridine converted into the hemisuccinate. The product, / 1 ⁵ -Pregnen-3 _j e, 2l-diol-20-oii-3-methyl ether-21-hemisuccinate, had the following physical constants: mp 171.6 ° to 173.8 °; λ ™ 2.9 to 3.3, 5.75, 5.81, 8.5.

This compound was then hydrogenated in the following way:

500 mg of a catalyst with 5% palladium on charcoal were ^{suspended in 10 cm 3 of} glacial acetic acid, and hydrogen was stirred in until the uptake of gas ceased.

* 5 500 mg of the ^{steroid dissolved in 25 cm 3 of} glacial acetic acid were then added. The hydrogenation proceeded very quickly. The uptake of 1 mole of hydrogen took about 2 hours. The catalyst was then removed by filtration through a diatomaceous earth filter aid (known under the trade name "Supercel") and the acetic acid was removed by vacuum distillation Products received.

The main product was the allopregnan ^ l-ol-S [beta] -methoxy-20-one-21-hemisuccinate, which had the following physical constants: mp 140 to 147 *; λ'Ζ ' 2.92, 3.0 to 3.3, 5.72, 5.75, 5.81, 8.5. The secondary product was pregnan-21-ol-3 / i-methoxy-20-one-21-] iemisuccinate. Treatment of these compounds with a basic sodium salt solution gives the corresponding sodium salts.

The allopregnan and pregnan-21-ol-3/9-methoxy-20-one-21-hemisuccinate was converted into the free 21 -hydroxyl compound with potassium carbonate in aqueous methanol convicted. Treatment of the compounds obtained with e.g. B. Aeetobromglucose and subsequent implementation with potassium carbonate gave the corresponding 21-glycosides. These represent amorphous solid substances that melt over a wide range from 275 to 290 " and infrared absorption maxima at 2.9 to 3.1, 5.9, 9.0 and 9.3 to 9.5 µ.

The conversion of the allopregnan- and pregnan-21-ol-3 /? -Niethoxy-20-one-21-hcmisuccinats into the 21-hydroxyl compound, acylation of the 21-position hydroxyl group with formation of the 21-glutaric acid half-ester and subsequent treatment with sodium carbonate gave this Sodium salt of Allopregnan- and Pregnan - 21-ol-3 / S-methoxy-20-one-21-hcmiglutarate, which melts at over 300 ° and intrared absorption maxiina at 2.9 to 3.1, 5.7, 5, 9, 8.0 and 9.1 μ. The sodium salt of allopregnan- and pregnan-21-ol-3jÖ-methoxy-20-one-21 -hemiplithalats can be prepared in a similar manner, which ^{melts over 300:} 'and infrared absorption maxima at 2.9 to 3.2.5 , 8, 5.9, 8.2 and 9.1 μ.

Example 2

zJ5-Pregncn-3 / ?, 21-cüol-20-on-21-acetate was applied to the in the same way as described above for the hydrogenation in Example 1, with a catalyst from Palladrum Hydrogenated charcoal. The mixture of steroids obtained was chromatographed in a column of synthetic Magnesium siphon using mixtures of Ether and benzene separately for washing out. Two products were obtained. The main product was AUopregnan-3 / J, 21-diol-20-on-21-acetate, the other product Pregnan-3 / ?, 21-diol-20-on-21-acetate. Each of these connections was made then treated by the following procedure described herein for illustration for the allo compound.

Allopregnan-3 / ?, 21-diol-20-one-2l -acetal was used at room temperature with p-toluenesulfonyl chloride and pyridine for

Introduction of a tosyl group in the 3/9 position treated. The product obtained, Alloprcgnan-3 / S, 21-diol-20-one-21-acetate-3-tosylate, had the following physical constants: mp 179.0 ° to 180.0 °; λ ™ 5.72, 5.82, 6.26, 8.11. By refluxing this compound with methanol according to the procedure described above in Example 1, the 3/3-position tos \ 'oil group was replaced by a 3-position methoxy group. During this reaction, the acetate group at the 21-position was saponified to an oxy group. This procedure gives allopregnan-21 -ol-Sct-methoxy ^ O-one. The Prcgnan-21 -ol-3rt-methoxy-20-one was obtained in a similar manner.

The treatment of λ · οη allopregnan-21-ol-3ft-methoxj ^r -20-one and its normal isomer with succinic anhydride and pyridine gives the 21-hemisuccinate, which is converted into the sodium salt by treatment with sodium carbonate.

In a similar manner, the sodium salt of Allopregnan and pregnane-2l-ol-3-niethoxy-20-on-21-hemiglutarats (it melts at about 300 ^c and has _a o infra-red absorption maxima at 2.9 to 3 , 1, 5.7, 5.9, 8.0 and 9.1 μ), also the sodium salt of allopregnan- and prcgnan-21-ol-3c ^ methoxy-20-one-21-heiniphthalats (it melts over 300 "and has infrared absorption maxima at 2.9 to 3.2, 5.8, 5.9, 8.2 and 9.1 μ). The AUopregnan- and pregnan-21-ol-3a-methoxy-20-one can also be converted into 21-glycosides according to the procedure explained in Example 1. These are amorphous solid substances which melt at about 275 to 290 ° and in the infrared range absorption maxima at 2.9 to 3.1, 5.9, 9 , 1 and 9.3 to 9.5 μ.

Claims (5)

Patent claims: 1. Process for the production of steroid compounds that have a calming effect on the central nervous system fertilizing the general form) CH. CH ,. low Alkoxy- CH ₃ | 0 45 δ « ⁵ in which E is an ionic ester group of the formula __ O - C - L - C - O "M ' ^! - 0 — C — L —NR ₃ ^T Z ~ ! I ο means in the L the remainders. - (CH,). ,, -, - O - (CH ₂ ) ,, - or - NH - (CII ₂ ) ,, -, η = 1 to 6 and M ⁺ the cations Na ^-1 ", K ⁺ or NR ₁ ⁺ , where R in the formulas given is hydrogen, an alkyl, oxyalkyl, acyloxyalkyl, aminoalkyl, aryl or aralkyl group with up to 10 carbon atoms each and 2 is a pharmacologically suitable anion, or in which E is a glycoside residue which is derived from mono- or disaccharides with 5 and 6 carbon atoms and the 5-position H atom is α- or ^ '-, characterized in that 5-pregnen-3 / ?, 21-diol-20-one 21-acetate with a p-'l "oluolsuJfonylhalogenid reacted, treating the obtained compound with a low molecular weight alkanol _x, then hydrogenated or the hydrogenation \> m the reaction with the p-toluenesulfonyl carries out the allopregnan or pregnan-3,21-diol-3-alkyl ether prepared in this way with an acetobromo mono- or disaccharide that does not contain more than 12 carbon atoms in the carbohydrate content contains, treated or acylated the allopregnan or pregnan-3,21-diol-3-alkyl ether and treated the product obtained with a basic agent. 2. The method according to claim 1, characterized in that there is used as p-toluenesulfonyl halide p-Toluenesulfonyl chloride is used. 3. The method according to claim 1 or 2, characterized in that that one uses methanol as the low molecular weight alcohol. 4. The method according to claim 1 to 3, characterized in that the hydrogenation with a Palladium-charcoal catalyst performs. 5. The method according to claim 1 to 4, characterized in that that acetobromo glucose is used as the acetobromosaccharide. 70 »810/341 12.